Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Charge-based immunoreceptor signalling in health and disease

Nature Reviews Immunology volume 25, pages 298–311 (2025)Cite this article

Subjects

Abstract

Immunoreceptors have crucial roles in sensing environmental signals and initiating immune responses to protect the host. Dysregulation of immunoreceptor signalling can therefore lead to a range of diseases, making immunoreceptor-based therapies a promising frontier in biomedicine. A common feature of various immunoreceptors is the basic-residue-rich sequence (BRS), which is a largely unexplored aspect of immunoreceptor signalling. The BRS is typically located in the cytoplasmic juxtamembrane region of immunoreceptors, where it forms dynamic interactions with neighbouring charged molecules to regulate signalling. Loss or gain of the basic residues in an immunoreceptor BRS has been linked to severe human diseases, such as immunodeficiency and autoimmunity. In this Perspective, we describe the role of BRSs in various immunoreceptors, elucidating their signalling mechanisms and biological functions. Furthermore, we highlight pathogenic mutations in immunoreceptor BRSs and discuss the potential of leveraging BRS signalling in engineered T cell-based therapies.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The basic-residue-rich sequence in membrane proteins.
Fig. 2: Signalling and functions of immunoreceptor basic-residue-rich sequences.
Fig. 3: Yin and yang of human basic-residue-rich sequence mutations.
Fig. 4: Translational strategies of basic-residue-rich sequence signalling in immune cell therapy.

Similar content being viewed by others

References

  1. Verdin, P. Top companies and drugs by sales in 2023. Nat. Rev. Drug. Discov. 23, 240 (2024).

    Article  CAS  PubMed  Google Scholar 

  2. June, C. H. & Sadelain, M. Chimeric antigen receptor therapy. N. Engl. J. Med. 379, 64–73 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hegde, P. S. & Chen, D. S. Top 10 challenges in cancer immunotherapy. Immunity 52, 17–35 (2020).

    Article  CAS  PubMed  Google Scholar 

  4. Billadeau, D. D. & Leibson, P. J. ITAMs versus ITIMs: striking a balance during cell regulation. J. Clin. Invest. 109, 161–168 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Yang, W. et al. Dynamic regulation of CD28 conformation and signaling by charged lipids and ions. Nat. Struct. Mol. Biol. 24, 1081–1092 (2017).

    Article  CAS  PubMed  Google Scholar 

  6. Xu, C. et al. Regulation of T cell receptor activation by dynamic membrane binding of the CD3ε cytoplasmic tyrosine-based motif. Cell 135, 702–713 (2008). This paper demonstrates that the electrostatic interactions between the BRS and acidic lipids sequester the adjacent tyrosine motif within the membrane.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Dobbins, J. et al. Binding of the cytoplasmic domain of CD28 to the plasma membrane inhibits lck recruitment and signaling. Sci. Signal. 9, ra75 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Deford-Watts, L. M. et al. The cytoplasmic tail of the T cell receptor CD3ε subunit contains a phospholipid-binding motif that regulates T cell functions. J. Immunol. 183, 1055–1064 (2009).

    Article  CAS  PubMed  Google Scholar 

  9. Li, L. et al. Ionic CD3–Lck interaction regulates the initiation of T-cell receptor signaling. Proc. Natl Acad. Sci. USA 114, E5891–E5899 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Wu, W. et al. Multiple signaling roles of CD3ε and its application in CAR-T cell therapy. Cell 182, 855–871 e823 (2020). This paper reports TCR–CD3 phosphorylation patterns and a rational design of CD3ε-based CARs.

    Article  CAS  PubMed  Google Scholar 

  11. Aivazian, D. & Stern, L. J. Phosphorylation of T cell receptor ζ is regulated by a lipid dependent folding transition. Nat. Struct. Biol. 7, 1023–1026 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Zhang, H., Cordoba, S. P., Dushek, O. & van der Merwe, P. A. Basic residues in the T-cell receptor ζ cytoplasmic domain mediate membrane association and modulate signaling. Proc. Natl Acad. Sci. USA 108, 19323–19328 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. DeFord-Watts, L. M. et al. The CD3 ζ subunit contains a phosphoinositide-binding motif that is required for the stable accumulation of TCR–CD3 complex at the immunological synapse. J. Immunol. 186, 6839–6847 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Chen, X. et al. Acidic phospholipids govern the enhanced activation of IgG-B cell receptor. Nat. Commun. 6, 8552 (2015).

    Article  CAS  PubMed  Google Scholar 

  15. Wen, M. et al. PD-L1 degradation is regulated by electrostatic membrane association of its cytoplasmic domain. Nat. Commun. 12, 5106 (2021). This paper demonstrates that the electrostatic interactions between the BRS and acidic lipids sequester the lysine ubiquitylation sites within the membrane.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sarangi, S. K., Lande, K. M. & Kumar, S. KIR signaling is regulated by electrostatic interaction of its cytosolic tail with the plasma membrane despite being neutral polyampholyte. Proc. Natl Acad. Sci. USA 120, e2212987120 (2023).

    Article  CAS  PubMed  Google Scholar 

  17. Cheng, H. et al. Conformational changes in the cytoplasmic region of KIR3DL1 upon interaction with SHP-2. Structure 27, 639–650 e632 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sigalov, A. B., Aivazian, D. A., Uversky, V. N. & Stern, L. J. Lipid-binding activity of intrinsically unstructured cytoplasmic domains of multichain immune recognition receptor signaling subunits. Biochemistry 45, 15731–15739 (2006).

    Article  CAS  PubMed  Google Scholar 

  19. Moes, B. et al. INPP5K controls the dynamic structure and signaling of wild-type and mutated, leukemia-associated IL-7 receptors. Blood 141, 1708–1717 (2023).

    Article  CAS  PubMed  Google Scholar 

  20. Dong, R. et al. Molecular dynamics of the recruitment of immunoreceptor signaling module DAP12 homodimer to lipid raft boundary regulated by PIP2. J. Phys. Chem. B 124, 504–510 (2020).

    Article  CAS  PubMed  Google Scholar 

  21. Sun, F. et al. Molecular mechanism for bidirectional regulation of CD44 for lipid raft affiliation by palmitoylations and PIP2. PLoS Comput. Biol. 16, e1007777 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Araya-Secchi, R. et al. The prolactin receptor scaffolds Janus kinase 2 via co-structure formation with phosphoinositide-4,5-bisphosphate. eLife 12, e84645 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Haxholm, G. W. et al. Intrinsically disordered cytoplasmic domains of two cytokine receptors mediate conserved interactions with membranes. Biochem. J. 468, 495–506 (2015).

    Article  CAS  PubMed  Google Scholar 

  24. Paddock, C. et al. Residues within a lipid-associated segment of the PECAM-1 cytoplasmic domain are susceptible to inducible, sequential phosphorylation. Blood 117, 6012–6023 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wu, W., Shi, X. & Xu, C. Regulation of T cell signalling by membrane lipids. Nat. Rev. Immunol. 16, 690–701 (2016).

    Article  CAS  PubMed  Google Scholar 

  26. Lorent, J. H. et al. Plasma membranes are asymmetric in lipid unsaturation, packing and protein shape. Nat. Chem. Biol. 16, 644–652 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Doktorova, M., Symons, J. L. & Levental, I. Structural and functional consequences of reversible lipid asymmetry in living membranes. Nat. Chem. Biol. 16, 1321–1330 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wen, Y., Vogt, V. M. & Feigenson, G. W. PI(4,5)P2 clustering and its impact on biological functions. Annu. Rev. Biochem. 90, 681–707 (2021).

    Article  CAS  PubMed  Google Scholar 

  29. Posor, Y., Jang, W. & Haucke, V. Phosphoinositides as membrane organizers. Nat. Rev. Mol. Cell Biol. 23, 797–816 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Schink, K. O., Tan, K. W. & Stenmark, H. Phosphoinositides in control of membrane dynamics. Annu. Rev. Cell Dev. Biol. 32, 143–171 (2016).

    Article  CAS  PubMed  Google Scholar 

  31. Zhukovsky, M. A., Filograna, A., Luini, A., Corda, D. & Valente, C. Phosphatidic acid in membrane rearrangements. FEBS Lett. 593, 2428–2451 (2019).

    Article  CAS  PubMed  Google Scholar 

  32. Golebiewska, U. et al. Membrane-bound basic peptides sequester multivalent (PIP2), but not monovalent (PS), acidic lipids. Biophys. J. 91, 588–599 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. McLaughlin, S. & Murray, D. Plasma membrane phosphoinositide organization by protein electrostatics. Nature 438, 605–611 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. van den Bogaart, G. et al. Membrane protein sequestering by ionic protein–lipid interactions. Nature 479, 552–555 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Xu, C. et al. A PIP2-derived amplification loop fuels the sustained initiation of B cell activation. Sci. Immunol. 2, eaan0787 (2017).

    Article  PubMed  Google Scholar 

  36. Wang, J. et al. Growth of B cell receptor microclusters is regulated by PIP2 and PIP3 equilibrium and Dock2 recruitment and activation. Cell Rep. 21, 2541–2557 (2017).

    Article  CAS  PubMed  Google Scholar 

  37. Wan, Z. et al. PI(4,5)P2 determines the threshold of mechanical force-induced B cell activation. J. Cell Biol. 217, 2565–2582 (2018). This paper demonstrates that the electrostatic interactions between the BRSs and PtdIns(4,5)P2 determine the mechanical force threshold required for BCR triggering.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Prakaash, D., Cook, G. P., Acuto, O. & Kalli, A. C. Multi-scale simulations of the T cell receptor reveal its lipid interactions, dynamics and the arrangement of its cytoplasmic region. PLoS Comput. Biol. 17, e1009232 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gagnon, E., Schubert, D. A., Gordo, S., Chu, H. H. & Wucherpfennig, K. W. Local changes in lipid environment of TCR microclusters regulate membrane binding by the CD3ε cytoplasmic domain. J. Exp. Med. 209, 2423–2439 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Chiu, T. Y. et al. INPP5E regulates CD3ζ enrichment at the immune synapse by phosphoinositide distribution control. Commun. Biol. 6, 911 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chouaki Benmansour, N. et al. Phosphoinositides regulate the TCR/CD3 complex membrane dynamics and activation. Sci. Rep. 8, 4966 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Yeung, T. et al. Membrane phosphatidylserine regulates surface charge and protein localization. Science 319, 210–213 (2008).

    Article  CAS  PubMed  Google Scholar 

  43. Zhou, Y. et al. Membrane potential modulates plasma membrane phospholipid dynamics and K-Ras signaling. Science 349, 873–876 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Connolly, A. et al. TMEM16F mediates bystander TCR–CD3 membrane dissociation at the immunological synapse and potentiates T cell activation. Sci. Signal. 14, eabb5146 (2021).

    Article  CAS  PubMed  Google Scholar 

  45. Duchardt, E., Sigalov, A. B., Aivazian, D., Stern, L. J. & Schwalbe, H. Structure induction of the T-cell receptor ζ-chain upon lipid binding investigated by NMR spectroscopy. Chembiochem 8, 820–827 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Sigalov, A. B. & Hendricks, G. M. Membrane binding mode of intrinsically disordered cytoplasmic domains of T cell receptor signaling subunits depends on lipid composition. Biochem. Biophys. Res. Commun. 389, 388–393 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zimmermann, K. et al. The cytosolic domain of T-cell receptor ζ associates with membranes in a dynamic equilibrium and deeply penetrates the bilayer. J. Biol. Chem. 292, 17746–17759 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Liang, W. et al. Enhancing the antitumor immunity of T cells by engineering the lipid-regulatory site of the TCR/CD3 complex. Cancer Immunol. Res. 11, 93–108 (2023).

    Article  CAS  PubMed  Google Scholar 

  49. Hartl, F. A. et al. Noncanonical binding of Lck to CD3ε promotes TCR signaling and CAR function. Nat. Immunol. 21, 902–913 (2020).

    Article  CAS  PubMed  Google Scholar 

  50. Rudd, C. E. How the discovery of the CD4/CD8–p56(lck) complexes changed immunology and immunotherapy. Front. Cell Dev. Biol. 9, 626095 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Carmo, A. M., Mason, D. W. & Beyers, A. D. Physical association of the cytoplasmic domain of CD2 with the tyrosine kinases p56lck and p59fyn. Eur. J. Immunol. 23, 2196–2201 (1993).

    Article  CAS  PubMed  Google Scholar 

  52. Raab, M., Yamamoto, M. & Rudd, C. E. The T-cell antigen CD5 acts as a receptor and substrate for the protein-tyrosine kinase p56lck. Mol. Cell Biol. 14, 2862–2870 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Xu, X. et al. Phase separation of chimeric antigen receptor promotes immunological synapse maturation persistent cytotoxicity. Preprint at SSRN https://doi.org/10.2139/ssrn.4634356 (2023).

  54. Glassman, C. R. et al. Structure of a Janus kinase cytokine receptor complex reveals the basis for dimeric activation. Science 376, 163–169 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wilmes, S. et al. Mechanism of homodimeric cytokine receptor activation and dysregulation by oncogenic mutations. Science 367, 643–652 (2020). This paper demonstrates that ligand binding induces a conformational change of the cytoplasmic juxtamembrane region of cytokine receptors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Brooks, A. J. et al. Mechanism of activation of protein kinase JAK2 by the growth hormone receptor. Science 344, 1249783 (2014).

    Article  PubMed  Google Scholar 

  57. Bugge, K. et al. A combined computational and structural model of the full-length human prolactin receptor. Nat. Commun. 7, 11578 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kassem, N. et al. Order and disorder — an integrative structure of the full-length human growth hormone receptor. Sci. Adv. 7, eabh3805 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Monks, C. R., Freiberg, B. A., Kupfer, H., Sciaky, N. & Kupfer, A. Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395, 82–86 (1998).

    Article  CAS  PubMed  Google Scholar 

  60. Campi, G., Varma, R. & Dustin, M. L. Actin and agonist mhc-peptide complex-dependent T cell receptor microclusters as scaffolds for signaling. J. Exp. Med. 202, 1031–1036 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Yokosuka, T. et al. Spatiotemporal regulation of T cell costimulation by TCR–CD28 microclusters and protein kinase C θ translocation. Immunity 29, 589–601 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Yokosuka, T. et al. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J. Exp. Med. 209, 1201–1217 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Krummel, M. F., Sjaastad, M. D., Wulfing, C. & Davis, M. M. Differential clustering of CD4 and CD3ζ during T cell recognition. Science 289, 1349–1352 (2000).

    Article  CAS  PubMed  Google Scholar 

  64. Liu, W., Wang, H. & Xu, C. Antigen receptor nanoclusters: small units with big functions. Trends Immunol. 37, 680–689 (2016).

    Article  CAS  PubMed  Google Scholar 

  65. Grakoui, A. et al. The immunological synapse: a molecular machine controlling T cell activation. Science 285, 221–227 (1999).

    Article  CAS  PubMed  Google Scholar 

  66. Kuokkanen, E., Sustar, V. & Mattila, P. K. Molecular control of B cell activation and immunological synapse formation. Traffic 16, 311–326 (2015).

    Article  CAS  PubMed  Google Scholar 

  67. Orange, J. S. Formation and function of the lytic NK-cell immunological synapse. Nat. Rev. Immunol. 8, 713–725 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Feske, S. Calcium signalling in lymphocyte activation and disease. Nat. Rev. Immunol. 7, 690–702 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Feske, S., Wulff, H. & Skolnik, E. Y. Ion channels in innate and adaptive immunity. Annu. Rev. Immunol. 33, 291–353 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Liu, C. S. C. et al. Piezo1 mechanosensors optimize human T cell activation. J. Immunol. 200, 1255–1260 (2018).

    Article  CAS  PubMed  Google Scholar 

  71. Solis, A. G. et al. Mechanosensation of cyclical force by PIEZO1 is essential for innate immunity. Nature 573, 69–74 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Shi, X. et al. Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids. Nature 493, 111–115 (2013). This paper demonstrates that Ca2+ directly neutralizes lipid negative charges, thereby disrupting BRS–lipid interactions.

    Article  PubMed  Google Scholar 

  73. Han, K., Kim, S. H., Venable, R. M. & Pastor, R. W. Design principles of PI(4,5)P2 clustering under protein-free conditions: specific cation effects and calcium–potassium synergy. Proc. Natl Acad. Sci. USA 119, e2202647119 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wang, Y. H. et al. Divalent cation-induced cluster formation by polyphosphoinositides in model membranes. J. Am. Chem. Soc. 134, 3387–3395 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zech, T. et al. Accumulation of raft lipids in T-cell plasma membrane domains engaged in TCR signalling. EMBO J. 28, 466–476 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Ren, Z. et al. Transient hydroxycholesterol treatment restrains TCR signaling to promote long-term immunity. Cell Chem. Biol. 31, 920–931 e926 (2024). This paper demonstrates that 7α-HC and cholesterol regulate BRS–lipid interactions in opposing ways and reports a sterol-based approach for enhancing memory populations in TCR–T cell products.

    Article  CAS  PubMed  Google Scholar 

  77. Chen, H. et al. Self-programmed dynamics of T cell receptor condensation. Proc. Natl Acad. Sci. USA 120, e2217301120 (2023). This paper demonstrates that the electrostatic interactions between the CD3ε BRS and LCK drive liquid–liquid phase separation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Guy, C. et al. LAG3 associates with TCR–CD3 complexes and suppresses signaling by driving co-receptor–Lck dissociation. Nat. Immunol. 23, 757–767 (2022). This paper reports that the tandem EP motif (glutamic acid–proline-rich tandem repeat) of LAG3 lowers local pH, thereby disrupting LCK interactions with BRS-containing coreceptors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Latour, S. & Veillette, A. Proximal protein tyrosine kinases in immunoreceptor signaling. Curr. Opin. Immunol. 13, 299–306 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Veillette, A., Latour, S. & Davidson, D. Negative regulation of immunoreceptor signaling. Annu. Rev. Immunol. 20, 669–707 (2002).

    Article  CAS  PubMed  Google Scholar 

  81. O’Neill, S. K. et al. Monophosphorylation of CD79a and CD79b ITAM motifs initiates a SHIP-1 phosphatase-mediated inhibitory signaling cascade required for B cell anergy. Immunity 35, 746–756 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Velasco Cardenas, R. M. et al. Harnessing CD3 diversity to optimize CAR T cells. Nat. Immunol. 24, 2135–2149 (2023). This paper exploits different CD3 chains in CAR design and demonstrates the role of the BRS–LCK interaction in CAR signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Kersh, E. N., Shaw, A. S. & Allen, P. M. Fidelity of T cell activation through multistep T cell receptor ζ phosphorylation. Science 281, 572–575 (1998).

    Article  CAS  PubMed  Google Scholar 

  84. Kersh, E. N., Kersh, G. J. & Allen, P. M. Partially phosphorylated T cell receptor ζ molecules can inhibit T cell activation. J. Exp. Med. 190, 1627–1636 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Zenner, G., Vorherr, T., Mustelin, T. & Burn, P. Differential and multiple binding of signal transducing molecules to the ITAMs of the TCR-ζ chain. J. Cell Biochem. 63, 94–103 (1996).

    Article  CAS  PubMed  Google Scholar 

  86. Ivashkiv, L. B. Cross-regulation of signaling by ITAM-associated receptors. Nat. Immunol. 10, 340–347 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Gaud, G. et al. CD3ζ ITAMs enable ligand discrimination and antagonism by inhibiting TCR signaling in response to low-affinity peptides. Nat. Immunol. 24, 2121–2134 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Pfirsch-Maisonnas, S. et al. Inhibitory ITAM signaling traps activating receptors with the phosphatase SHP-1 to form polarized “inhibisome” clusters. Sci. Signal. 4, ra24 (2011).

    Article  PubMed  Google Scholar 

  89. Morris, R., Kershaw, N. J. & Babon, J. J. The molecular details of cytokine signaling via the JAK/STAT pathway. Protein Sci. 27, 1984–2009 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Guo, X. et al. Lipid-dependent conformational dynamics underlie the functional versatility of T-cell receptor. Cell Res. 27, 505–525 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Jin, H., Liu, D., Ni, Y., Wang, H. & Long, D. Quantitative ensemble interpretation of membrane paramagnetic relaxation enhancement (mPRE) for studying membrane-associated intrinsically disordered proteins. J. Am. Chem. Soc. 146, 791–800 (2024).

    Article  CAS  PubMed  Google Scholar 

  92. Wang, H. et al. Probing transient release of membrane-sequestered tyrosine-based signaling motif by solution NMR spectroscopy. J. Phys. Chem. Lett. 8, 3765–3769 (2017).

    Article  CAS  PubMed  Google Scholar 

  93. Hermiston, M. L., Xu, Z. & Weiss, A. CD45: a critical regulator of signaling thresholds in immune cells. Annu. Rev. Immunol. 21, 107–137 (2003).

    Article  CAS  PubMed  Google Scholar 

  94. Sasmal, D. K. et al. TCR-pMHC bond conformation controls TCR ligand discrimination. Cell Mol. Immunol. 17, 203–217 (2020).

    Article  CAS  PubMed  Google Scholar 

  95. Alberti, S., Gladfelter, A. & Mittag, T. Considerations and challenges in studying liquid-liquid phase separation and biomolecular condensates. Cell 176, 419–434 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Rudd, C. E. & Schneider, H. Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nat. Rev. Immunol. 3, 544–556 (2003).

    Article  CAS  PubMed  Google Scholar 

  97. King, P. D. et al. Analysis of CD28 cytoplasmic tail tyrosine residues as regulators and substrates for the protein tyrosine kinases, EMT and LCK. J. Immunol. 158, 580–590 (1997).

    Article  CAS  PubMed  Google Scholar 

  98. Zhu, C., Chen, W., Lou, J., Rittase, W. & Li, K. Mechanosensing through immunoreceptors. Nat. Immunol. 20, 1269–1278 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Wan, Z. et al. The activation of IgM- or isotype-switched IgG- and IgE-BCR exhibits distinct mechanical force sensitivity and threshold. eLife 4, e06925 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Shen, Z. et al. Conformational change within the extracellular domain of B cell receptor in B cell activation upon antigen binding. eLife 8, e42271 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Engels, N. et al. Recruitment of the cytoplasmic adaptor Grb2 to surface IgG and IgE provides antigen receptor-intrinsic costimulation to class-switched B cells. Nat. Immunol. 10, 1018–1025 (2009).

    Article  CAS  PubMed  Google Scholar 

  102. Kim, S. T. et al. The αβ T cell receptor is an anisotropic mechanosensor. J. Biol. Chem. 284, 31028–31037 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Liu, B., Chen, W., Evavold, B. D. & Zhu, C. Accumulation of dynamic catch bonds between TCR and agonist peptide-MHC triggers T cell signaling. Cell 157, 357–368 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Bettini, M. L. et al. Membrane association of the CD3ε signaling domain is required for optimal T cell development and function. J. Immunol. 193, 258–267 (2014).

    Article  CAS  PubMed  Google Scholar 

  105. Duerr, R. H. et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314, 1461–1463 (2006). This paper describes a mutation of basic residue in the juxtamembrane region of IL-23R and its association with inflammatory bowel disease.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Momozawa, Y. et al. Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease. Nat. Genet. 43, 43–47 (2011).

    Article  CAS  PubMed  Google Scholar 

  107. Di Meglio, P. et al. The IL23R A/Gln381 allele promotes IL-23 unresponsiveness in human memory T-helper 17 cells and impairs Th17 responses in psoriasis patients. J. Invest. Dermatol. 133, 2381–2389 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Pidasheva, S. et al. Functional studies on the IBD susceptibility gene IL23R implicate reduced receptor function in the protective genetic variant R381Q. PLoS ONE 6, e25038 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Sarin, R., Wu, X. & Abraham, C. Inflammatory disease protective R381Q IL23 receptor polymorphism results in decreased primary CD4+ and CD8+ human T-cell functional responses. Proc. Natl Acad. Sci. USA 108, 9560–9565 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Di Meglio, P. et al. The IL23R R381Q gene variant protects against immune-mediated diseases by impairing IL-23-induced Th17 effector response in humans. PLoS ONE 6, e17160 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Sun, R., Hedl, M. & Abraham, C. IL23 induces IL23R recycling and amplifies innate receptor-induced signalling and cytokines in human macrophages, and the IBD-protective IL23R R381Q variant modulates these outcomes. Gut 69, 264–273 (2020).

    Article  CAS  PubMed  Google Scholar 

  112. Sun, R. & Abraham, C. IL23 promotes antimicrobial pathways in human macrophages, which are reduced with the IBD-protective IL23R R381Q variant. Cell Mol. Gastroenterol. Hepatol. 10, 673–697 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Kerner, G. et al. Genetic adaptation to pathogens and increased risk of inflammatory disorders in post-neolithic europe. Cell Genom. 3, 100248 (2023). This paper reports the R381Q mutation of IL-23R as a candidate variant for negative selection in European populations.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Shim, J. O. & Seo, J. K. Very early-onset inflammatory bowel disease (IBD) in infancy is a different disease entity from adult-onset IBD; one form of interleukin-10 receptor mutations. J. Hum. Genet. 59, 337–341 (2014).

    Article  CAS  PubMed  Google Scholar 

  115. Begue, B. et al. Defective IL10 signaling defining a subgroup of patients with inflammatory bowel disease. Am. J. Gastroenterol. 106, 1544–1555 (2011).

    Article  CAS  PubMed  Google Scholar 

  116. Aschenbrenner, D. et al. Pathogenic interleukin-10 receptor α variants in humans — balancing natural selection and clinical implications. J. Clin. Immunol. 43, 495–511 (2023).

    Article  CAS  PubMed  Google Scholar 

  117. Castigli, E. et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat. Genet. 37, 829–834 (2005).

    Article  CAS  PubMed  Google Scholar 

  118. Salzer, U. et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat. Genet. 37, 820–828 (2005). Together with the paper by Castigli et al. (2005), this paper reports a loss of basic residue mutation in the juxtamembrane region of TACI and its role in common variable immunodeficiency.

    Article  CAS  PubMed  Google Scholar 

  119. Pan-Hammarstrom, Q. et al. Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat. Genet. 39, 429–430 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  120. Castigli, E. et al. Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat. Genet. 39, 430–431 (2007).

    Article  CAS  PubMed  Google Scholar 

  121. de Mattos Barbosa, M. G. et al. TNFRSF13B genotypes control immune-mediated pathology by regulating the functions of innate B cells. JCI Insight 6, e150483 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Salzer, U. et al. Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes. Blood 113, 1967–1976 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Xia, X. Z. et al. TACI is a TRAF-interacting receptor for TALL-1, a tumor necrosis factor family member involved in B cell regulation. J. Exp. Med. 192, 137–143 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Bacchelli, C. et al. The C76R transmembrane activator and calcium modulator cyclophilin ligand interactor mutation disrupts antibody production and B-cell homeostasis in heterozygous and homozygous mice. J. Allergy Clin. Immunol. 127, 1253–1259 e1213 (2011).

    Article  CAS  PubMed  Google Scholar 

  125. Fried, A. J., Rauter, I., Dillon, S. R., Jabara, H. H. & Geha, R. S. Functional analysis of transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) mutations associated with common variable immunodeficiency. J. Allergy Clin. Immunol. 128, 226–228.e221 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Watanabe-Smith, K. et al. Discovery and functional characterization of a germline, CSF2RB-activating mutation in leukemia. Leukemia 30, 1950–1953 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Compagno, M. et al. Mutations of multiple genes cause deregulation of NF-κB in diffuse large B-cell lymphoma. Nature 459, 717–721 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Alankus, B. et al. Pathological rank signaling in B cells drives autoimmunity and chronic lymphocytic leukemia. J. Exp. Med. 218, e20200517 (2021).

    Article  CAS  PubMed  Google Scholar 

  129. Boggio, E. et al. Mutation of FAS, XIAP, and UNC13D genes in a patient with a complex lymphoproliferative phenotype. Pediatrics 132, e1052–e1058 (2013).

    Article  PubMed  Google Scholar 

  130. Campagnoli, M. F. et al. The broad spectrum of autoimmune lymphoproliferative disease: molecular bases, clinical features and long-term follow-up in 31 patients. Haematologica 91, 538–541 (2006).

    CAS  PubMed  Google Scholar 

  131. Ruan, W., Lee, C. T. & Desbarats, J. A novel juxtamembrane domain in tumor necrosis factor receptor superfamily molecules activates Rac1 and controls neurite growth. Mol. Biol. Cell 19, 3192–3202 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Poissonnier, A. et al. CD95-mediated calcium signaling promotes T helper 17 trafficking to inflamed organs in lupus-prone mice. Immunity 45, 209–223 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Poissonnier, A. et al. Disrupting the CD95-PLCγ1 interaction prevents Th17-driven inflammation. Nat. Chem. Biol. 14, 1079–1089 (2018).

    Article  CAS  PubMed  Google Scholar 

  134. Chen, X. et al. An autoimmune disease variant of IgG1 modulates B cell activation and differentiation. Science 362, 700–705 (2018). This paper reports a gain of basic residue mutation in the cytoplasmic region of human IgG1 and its pathogenic role in autoimmunity.

    Article  CAS  PubMed  Google Scholar 

  135. Yang, B. et al. An Asia-specific variant of human IgG1 represses colorectal tumorigenesis by shaping the tumor microenvironment. J. Clin. Invest. 132, e153454 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Sun, W. et al. An IGHG1 variant exhibits polarized prevalence and confers enhanced IgG1 antibody responses against life-threatening organisms. Nat. Immunol. 25, 1809–1819 (2024).

    Article  CAS  PubMed  Google Scholar 

  137. Xu, J. et al. Mechanistic insights into the inhibition of a common CTLA-4 gene mutation in the cytoplasmic domain. Molecules 29, 1330 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Baulu, E., Gardet, C., Chuvin, N. & Depil, S. TCR-engineered T cell therapy in solid tumors: state of the art and perspectives. Sci. Adv. 9, eadf3700 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Weber, E. W., Maus, M. V. & Mackall, C. L. The emerging landscape of immune cell therapies. Cell 181, 46–62 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Chan, J. D. et al. Cellular networks controlling T cell persistence in adoptive cell therapy. Nat. Rev. Immunol. 21, 769–784 (2021).

    Article  CAS  PubMed  Google Scholar 

  141. Shah, N. N. & Fry, T. J. Mechanisms of resistance to CAR T cell therapy. Nat. Rev. Clin. Oncol. 16, 372–385 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Rafiq, S., Hackett, C. S. & Brentjens, R. J. Engineering strategies to overcome the current roadblocks in CAR T cell therapy. Nat. Rev. Clin. Oncol. 17, 147–167 (2020).

    Article  PubMed  Google Scholar 

  143. Wang, H., Huang, Y. & Xu, C. Charging CAR by electrostatic power. Immunol. Rev. 320, 138–146 (2023).

    Article  CAS  PubMed  Google Scholar 

  144. Chen, J. et al. Tuning charge density of chimeric antigen receptor optimizes tonic signaling and CAR-T cell fitness. Cell Res. 33, 341–354 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Yang, W. et al. Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism. Nature 531, 651–655 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Yan, C. et al. Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity. Cancer Cell 41, 1276–1293.e1211 (2023).

    Article  CAS  PubMed  Google Scholar 

  147. Waddington, K. E. et al. LXR directly regulates glycosphingolipid synthesis and affects human CD4+ T cell function. Proc. Natl Acad. Sci. USA 118, e2017394118 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Takahashi, H. et al. Cholesterol 25-hydroxylase is a metabolic switch to constrain T cell-mediated inflammation in the skin. Sci. Immunol. 6, eabb6444 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Baek, A. E. et al. The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells. Nat. Commun. 8, 864 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  150. Li, M. et al. Enhanced chemo-immunotherapy against melanoma by inhibition of cholesterol esterification in CD8+ T cells. Nanomedicine 14, 2541–2550 (2018).

    Article  CAS  PubMed  Google Scholar 

  151. Pan, J. et al. Potentiation of Kras peptide cancer vaccine by avasimibe, a cholesterol modulator. eBioMedicine 49, 72–81 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Chen, X., Song, Q., Xia, L. & Xu, X. Synergy of dendritic cell vaccines and avasimibe in treatment of head and neck cancer in mice. Med. Sci. Monit. 23, 4471–4476 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Zhao, L. et al. Inhibition of cholesterol esterification enzyme enhances the potency of human chimeric antigen receptor T cells against pancreatic carcinoma. Mol. Ther. Oncolyt. 16, 262–271 (2020).

    Article  CAS  Google Scholar 

  154. Zhao, L. et al. Cholesterol esterification enzyme inhibition enhances antitumor effects of human chimeric antigen receptors modified T cells. J. Immunother. 41, 45–52 (2018).

    Article  CAS  PubMed  Google Scholar 

  155. Ma, S. et al. Avasimibe can cooperate with a DC-targeting and integration-deficient lentivector to induce stronger HBV specific T cytotoxic response by regulating cholesterol metabolism. Antivir. Res. 216, 105662 (2023).

    Article  CAS  PubMed  Google Scholar 

  156. Hao, M. et al. Combination of metabolic intervention and T cell therapy enhances solid tumor immunotherapy. Sci. Transl. Med. 12, eaaz6667 (2020).

    Article  CAS  PubMed  Google Scholar 

  157. Salter, A. I. et al. Comparative analysis of TCR and CAR signaling informs CAR designs with superior antigen sensitivity and in vivo function. Sci. Signal. 14, eabe2606 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Roybal, K. T. et al. Engineering T cells with customized therapeutic response programs using synthetic Notch receptors. Cell 167, 419–432.e416 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Morsut, L. et al. Engineering customized cell sensing and response behaviors using synthetic Notch receptors. Cell 164, 780–791 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Zhu, I. et al. Modular design of synthetic receptors for programmed gene regulation in cell therapies. Cell 185, 1431–1443.e1416 (2022). This paper reports that the BRS is the best juxtamembrane region for SNIPR activity and tuning BRS charges influences receptor activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Jenkins, B. J., Blake, T. J. & Gonda, T. J. Saturation mutagenesis of the β subunit of the human granulocyte-macrophage colony-stimulating factor receptor shows clustering of constitutive mutations, activation of ERK MAP kinase and STAT pathways, and differential β subunit tyrosine phosphorylation. Blood 92, 1989–2002 (1998).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

C.X. is funded by a Ministry of Science and Technology of the Peoples’s Republic of China (MOST) grant (2023YFA1800200), a Chinese Academy of Sciences (CAS) grant (YSBR-014) and a Science and Technology Commission of Shanghai Municipality (STCSM) grant (23J21901300). X.S. is funded by a MOST grant (2023YFA0915700). We thank H. Wang for discussion and proof-reading.

Author information

Authors and Affiliations

  1. Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China

    Xiaoshan Shi

  2. Key Laboratory of Multi-Cell Systems, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai, China

    Xing He & Chenqi Xu

Authors
  1. Xiaoshan Shi
    View author publications

    Search author on:PubMed Google Scholar

  2. Xing He
    View author publications

    Search author on:PubMed Google Scholar

  3. Chenqi Xu
    View author publications

    Search author on:PubMed Google Scholar

Contributions

C.X. composed the paper. X.S. and X.H. contributed to discussions. C.X. and X.S. wrote the paper and X.H. prepared the figures. X.S. collected the references and performed bioinformatic analyses.

Corresponding authors

Correspondence to Xiaoshan Shi or Chenqi Xu.

Ethics declarations

Competing interests

The authors have patents filed for E-CAR and cholesterol modulation strategies.

Peer review

Peer review information

Nature Reviews Immunology thanks Susana Minguet, who co-reviewed with Nadine Woessner, Wanli Liu, who co-reviewed with Chenguang Xu, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

Uniprot: https://www.uniprot.org/

Xu lab: http://xulab.sibcb.ac.cn/

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shi, X., He, X. & Xu, C. Charge-based immunoreceptor signalling in health and disease. Nat Rev Immunol 25, 298–311 (2025). https://doi.org/10.1038/s41577-024-01105-6

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41577-024-01105-6

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing