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The precursors of CD8+ tissue resident memory T cells: from lymphoid organs to infected tissues

Nature Reviews Immunology volume 22, pages 283–293 (2022)Cite this article

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Abstract

CD8+ tissue resident memory T cells (TRM cells) are essential for immune defence against pathogens and malignancies, and the molecular processes that lead to TRM cell formation are therefore of substantial biomedical interest. Prior work has demonstrated that signals present in the inflamed tissue micro-environment can promote the differentiation of memory precursor cells into mature TRM cells, and it was therefore long assumed that TRM cell formation adheres to a ‘local divergence’ model, in which TRM cell lineage decisions are exclusively made within the tissue. However, a growing body of work provides evidence for a ‘systemic divergence’ model, in which circulating T cells already become preconditioned to preferentially give rise to the TRM cell lineage, resulting in the generation of a pool of TRM cell-poised T cells within the lymphoid compartment. Here, we review the emerging evidence that supports the existence of such a population of circulating TRM cell progenitors, discuss current insights into their formation and highlight open questions in the field.

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Fig. 1: Models of TRM cell lineage divergence.
Fig. 2: Properties of TRM cell-poised T cells.
Fig. 3: Signals within lymphoid tissues that poise T cells towards TRM cell development.
Fig. 4: Distinguishing characteristics of TRM cell-poised memory precursor cells within the circulation.

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References

  1. Obar, J. J., Khanna, K. M. & Lefrançois, L. Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection. Immunity 28, 859–869 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Abdelsamed, H. A., Zebley, C. C. & Youngblood, B. Epigenetic maintenance of acquired gene expression programs during memory CD8 T cell homeostasis. Front. Immunol. 9, 6 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Jameson, S. C. & Masopust, D. Understanding subset diversity in T cell memory. Immunity 48, 214–226 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gattinoni, L. et al. A human memory T cell subset with stem cell-like properties. Nat. Med. 17, 1290–1297 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Olson, J. A., McDonald-Hyman, C., Jameson, S. C. & Hamilton, S. E. Effector-like CD8+ T cells in the memory population mediate potent protective. Immun. Immunity 38, 1250–1260 (2013).

    Article  CAS  Google Scholar 

  6. Gerlach, C. et al. The chemokine receptor CX3CR1 defines three antigen-experienced CD8 T cell subsets with distinct roles in immune surveillance and homeostasis. Immunity 45, 1270–1284 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Osborn, J. F. et al. Enzymatic synthesis of core 2 O-glycans governs the tissue-trafficking potential of memory CD8+ T cells. Sci. Immunol. 2, eaan6049 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Buggert, M. et al. The identity of human tissue-emigrant CD8+ T cells. Cell 183, 1946–1961.e15 (2020).

    Article  CAS  PubMed  Google Scholar 

  9. Thome, J. J. C. et al. Spatial map of human T cell compartmentalization and maintenance over decades of life. Cell 159, 814–828 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Dijkgraaf, F. E. et al. Tissue patrol by resident memory CD8+ T cells in human skin. Nat. Immunol. 20, 756–764 (2019).

    Article  CAS  PubMed  Google Scholar 

  11. Ariotti, S. et al. Tissue-resident memory CD8+ T cells continuously patrol skin epithelia to quickly recognize local antigen. Proc. Natl Acad. Sci. USA 109, 19739–19744 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ariotti, S. et al. Skin-resident memory CD8+ T cells trigger a state of tissue-wide pathogen alert. Science 346, 101–105 (2014).

    Article  CAS  PubMed  Google Scholar 

  13. Schenkel, J. M. et al. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science 346, 98–101 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Pan, Y. et al. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 543, 252–256 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Masopust, D., Vezys, V., Wherry, E. J., Barber, D. L. & Ahmed, R. Cutting edge: gut microenvironment promotes differentiation of a unique memory CD8 T cell population. J. Immunol. 176, 2079–2083 (2006).

    Article  CAS  PubMed  Google Scholar 

  16. Hoekstra, M. E., Vijver, S. V. & Schumacher, T. N. Modulation of the tumor micro-environment by CD8+ T cell-derived cytokines. Curr. Opin. Immunol. 69, 65–71 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hombrink, P. et al. Programs for the persistence, vigilance and control of human CD8+ lung-resident memory T cells. Nat. Immunol. 17, 1467–1478 (2016).

    Article  CAS  PubMed  Google Scholar 

  18. Yang, Q. et al. Cutting edge: characterization of human tissue-resident memory T cells at different infection sites in patients with tuberculosis. J. Immunol. https://doi.org/10.4049/jimmunol.1901326 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Steinbach, K. et al. Brain-resident memory T cells represent an autonomous cytotoxic barrier to viral infection. J. Exp. Med. 213, 1571–1587 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kiniry, B. E. et al. Predominance of weakly cytotoxic, T-betLowEomesNeg CD8+ T-cells in human gastrointestinal mucosa: implications for HIV infection. Mucosal Immunol. 10, 1008–1020 (2017).

    Article  CAS  PubMed  Google Scholar 

  21. Kiniry, B. E. et al. Differential expression of CD8+ T cell cytotoxic effector molecules in blood and gastrointestinal mucosa in HIV-1 infection. J. Immunol. https://doi.org/10.4049/jimmunol.1701532 (2018).

    Article  PubMed  Google Scholar 

  22. Seidel, J. A. et al. Skin resident memory CD8+ T cells are phenotypically and functionally distinct from circulating populations and lack immediate cytotoxic function: phenotype and function of cutaneous T cells. Clin. Exp. Immunol. 194, 79–92 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Smolders, J. et al. Tissue-resident memory T cells populate the human brain. Nat. Commun. 9, 4593 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Frizzell, H. et al. Organ-specific isoform selection of fatty acid-binding proteins in tissue-resident lymphocytes. Sci. Immunol. 5, eaay9283 (2020).

    Article  CAS  PubMed  Google Scholar 

  25. Hayward, S. L. et al. Environmental cues regulate epigenetic reprogramming of airway-resident memory CD8+ T cells. Nat. Immunol. 21, 309–320 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Skon, C. N. et al. Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells. Nat. Immunol. 14, 1285–1293 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mueller, S. N. & Mackay, L. K. Tissue-resident memory T cells: local specialists in immune defence. Nat. Rev. Immunol. 16, 79–89 (2016).

    Article  CAS  PubMed  Google Scholar 

  28. Walsh, D. A. et al. The functional requirement for CD69 in establishment of resident memory CD8+ T cells varies with tissue location. J. Immunol. 203, 946–955 (2019).

    Article  CAS  PubMed  Google Scholar 

  29. Steinert, E. M. et al. Quantifying memory CD8 T cells reveals regionalization of immunosurveillance. Cell 161, 737–749 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Beura, L. K. et al. T cells in nonlymphoid tissues give rise to lymph-node-resident memory T cells. Immunity 48, 327–338.e5 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Buggert, M. et al. Identification and characterization of HIV-specific resident memory CD8+ T cells in human lymphoid tissue. Sci. Immunol. 3, eaar4526 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  32. Fonseca, R. et al. Developmental plasticity allows outside-in immune responses by resident memory T cells. Nat. Immunol. 21, 412–421 (2020). This study shows that TRM cells can rejoin the circulation upon activation, while preserving a TRM cell-like phenotype and a high propensity to again form TRM cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jiang, X. et al. Skin infection generates non-migratory memory CD8+ TRM cells providing global skin immunity. Nature 483, 227–231 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gebhardt, T. et al. Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virus. Nat. Immunol. 10, 524–530 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Enamorado, M. et al. Enhanced anti-tumour immunity requires the interplay between resident and circulating memory CD8+ T cells. Nat. Commun. 8, 16073 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Park, S. L. et al. Tissue-resident memory CD8+ T cells promote melanoma-immune equilibrium in skin. Nature 565, 366–371 (2019).

    Article  CAS  PubMed  Google Scholar 

  37. Strickley, J. D. et al. Immunity to commensal papillomaviruses protects against skin cancer. Nature 575, 519–522 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Clarke, J. et al. Single-cell transcriptomic analysis of tissue-resident memory T cells in human lung cancer. J. Exp. Med. 216, 2128–2149 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) et al. Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat. Med. 24, 986–993 (2018).

    Article  CAS  Google Scholar 

  40. Luoma, A. M. et al. Molecular pathways of colon inflammation induced by cancer immunotherapy. Cell 182, 655–671.e22 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Richmond, J. M. et al. Antibody blockade of IL-15 signaling has the potential to durably reverse vitiligo. Sci. Transl. Med. 10, eaam7710 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  42. Kurihara, K., Fujiyama, T., Phadungsaksawasdi, P., Ito, T. & Tokura, Y. Significance of IL-17A-producing CD8+CD103+ skin resident memory T cells in psoriasis lesion and their possible relationship to clinical course. J. Dermatol. Sci. 95, 21–27 (2019).

    Article  CAS  PubMed  Google Scholar 

  43. Gallais Sérézal, I. et al. A skewed pool of resident T cells triggers psoriasis-associated tissue responses in never-lesional skin from patients with psoriasis. J. Allergy Clin. Immunol. 143, 1444–1454 (2019).

    Article  PubMed  CAS  Google Scholar 

  44. Clark, R. A. Resident memory T cells in human health and disease. Sci. Transl. Med. 7, 269rv1–269rv1 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. de Leur, K. et al. Characterization of donor and recipient CD8+ tissue-resident memory T cells in transplant nephrectomies. Sci. Rep. 9, 5984 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Dijkgraaf, F. E., Kok, L. & Schumacher, T. N. M. Formation of tissue-resident CD8+ T-cell memory. Cold Spring Harb. Perspect. Biol. https://doi.org/10.1101/cshperspect.a038117 (2021).

    Article  PubMed  Google Scholar 

  47. Masopust, D. et al. Dynamic T cell migration program provides resident memory within intestinal epithelium. J. Exp. Med. 207, 553–564 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kurd, N. S. et al. Early precursors and molecular determinants of tissue-resident memory CD8+ T lymphocytes revealed by single-cell RNA sequencing. Sci. Immunol. 5, eaaz6894 (2020). This work, through single-cell transcriptome sequencing of CD8+ T cells in the spleen and gut responding to LCMV infection, delineates the transcriptional differences between T cells in the spleen and the gut, and between T cells within these organs at different stages of the immune response.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Milner, J. J. et al. Runx3 programs CD8+ T cell residency in non-lymphoid tissues and tumours. Nature 552, 253–257 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kaech, S. M. & Cui, W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat. Rev. Immunol. 12, 749–761 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Sheridan, B. S. et al. Oral infection drives a distinct population of intestinal resident memory CD8+ T cells with enhanced protective function. Immunity 40, 747–757 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Mackay, L. K. et al. The developmental pathway for CD103+CD8+ tissue-resident memory T cells of skin. Nat. Immunol. 14, 1294–1301 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Milner, J. J. et al. Heterogenous populations of tissue-resident CD8+ T cells are generated in response to infection and malignancy. Immunity 52, 808–824.e7 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Gray, S. M., Amezquita, R. A., Guan, T., Kleinstein, S. H. & Kaech, S. M. Polycomb repressive complex 2-mediated chromatin repression guides effector CD8+ T cell terminal differentiation and loss of multipotency. Immunity 46, 596–608 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Kakaradov, B. et al. Early transcriptional and epigenetic regulation of CD8+ T cell differentiation revealed by single-cell RNA sequencing. Nat. Immunol. 18, 422–432 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Muschaweckh, A. et al. Antigen-dependent competition shapes the local repertoire of tissue-resident memory CD8+ T cells. J. Exp. Med. 213, 3075–3086 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wakim, L. M., Smith, J., Caminschi, I., Lahoud, M. H. & Villadangos, J. A. Antibody-targeted vaccination to lung dendritic cells generates tissue-resident memory CD8 T cells that are highly protective against influenza virus infection. Mucosal Immunol. 8, 1060–1071 (2015).

    Article  CAS  PubMed  Google Scholar 

  58. Khan, T. N., Mooster, J. L., Kilgore, A. M., Osborn, J. F. & Nolz, J. C. Local antigen in nonlymphoid tissue promotes resident memory CD8+ T cell formation during viral infection. J. Exp. Med. 213, 951–966 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lauron, E. J. et al. Viral MHCI inhibition evades tissue-resident memory T cell formation and responses. J. Exp. Med. 216, 117–132 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. McMaster, S. R. et al. Pulmonary antigen encounter regulates the establishment of tissue-resident CD8 memory T cells in the lung airways and parenchyma. Mucosal Immunol. 11, 1071–1078 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Adachi, T. et al. Hair follicle-derived IL-7 and IL-15 mediate skin-resident memory T cell homeostasis and lymphoma. Nat. Med. 21, 1272–1279 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Mackay, L. K. et al. T-box transcription factors combine with the cytokines TGF-β and IL-15 to control tissue-resident memory T cell fate. Immunity 43, 1101–1111 (2015).

    Article  CAS  PubMed  Google Scholar 

  63. McGill, J., Van Rooijen, N. & Legge, K. L. IL-15 trans-presentation by pulmonary dendritic cells promotes effector CD8 T cell survival during influenza virus infection. J. Exp. Med. 207, 521–534 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Hirai, T. et al. Keratinocyte-mediated activation of the cytokine TGF-β maintains skin recirculating memory CD8+ T cells. Immunity 50, 1249–1261.e5 (2019). This work demonstrates that circulating memory T cells can migrate through the skin and that the persistence of these cells is mediated by TGFβ in the skin, indicative that signals in NLTs can shape the circulating T cell pool.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Mohammed, J. et al. Stromal cells control the epithelial residence of DCs and memory T cells by regulated activation of TGF-β. Nat. Immunol. 17, 414–421 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Casey, K. A. et al. Antigen-independent differentiation and maintenance of effector-like resident memory T cells in tissues. J. Immunol. 188, 4866–4875 (2012).

    Article  CAS  PubMed  Google Scholar 

  67. Nath, A. P. et al. Comparative analysis reveals a role for TGF-β in shaping the residency-related transcriptional signature in tissue-resident memory CD8+ T cells. PLoS ONE 14, e0210495 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Zhang, N. & Bevan, M. J. Transforming growth factor-β signaling controls the formation and maintenance of gut-resident memory T cells by regulating migration and retention. Immunity 39, 687–696 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. McLaren, J. E. et al. IL-33 augments virus-specific memory T cell inflation and potentiates the efficacy of an attenuated cytomegalovirus-based vaccine. J. Immunol. 202, 943–955 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ren, H. M. et al. IL-21 from high-affinity CD4 T cells drives differentiation of brain-resident CD8 T cells during persistent viral infection. Sci. Immunol. 5, eabb5590 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Pizzolla, A. et al. Resident memory CD8 + T cells in the upper respiratory tract prevent pulmonary influenza virus infection. Sci. Immunol. 2, eaam6970 (2017).

    Article  PubMed  Google Scholar 

  72. Schenkel, J. M. et al. IL-15-independent maintenance of tissue-resident and boosted effector memory CD8 T cells. J. Immunol. 196, 3920–3926 (2016).

    Article  CAS  PubMed  Google Scholar 

  73. Behr, F. M. et al. Blimp-1 rather than hobit drives the formation of tissue-resident memory CD8+ T cells in the lungs. Front. Immunol. 10, 400 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Mackay, L. K. et al. Hobit and Blimp1 instruct a universal transcriptional program of tissue residency in lymphocytes. Science 352, 459–463 (2016).

    Article  CAS  PubMed  Google Scholar 

  75. Herndler-Brandstetter, D. et al. KLRG1+ effector CD8+ T cells lose KLRG1, differentiate into all memory T cell lineages, and convey enhanced protective immunity. Immunity 48, 716–729.e8 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Kok, L. et al. A committed tissue-resident memory T cell precursor within the circulating CD8+ effector T cell pool. J. Exp. Med. 217, e20191711 (2020). This study, through a combination of lineage tracing and single-cell transcriptomics, reveals the existence of circulating effector T cells that display transcriptomic features of mature TRM cells and that possess a heightened potential to form TRM cells in mouse skin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Gaide, O. et al. Common clonal origin of central and resident memory T cells following skin immunization. Nat. Med. 21, 647–653 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Yu, C. I. et al. Human CD1c+ dendritic cells drive the differentiation of CD103+CD8+ mucosal effector T cells via the cytokine TGF-β. Immunity 38, 818–830 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Bourdely, P. et al. Transcriptional and functional analysis of CD1c+ human dendritic cells identifies a CD163+ subset priming CD8+CD103+ T cells. Immunity 53, 335–352.e8 (2020). This study describes a novel human dendritic cell subset, marked by CD1c and CD163 expression, that upon naive T cell priming drives the acquisition of phenotypic and transcriptomic features of human TRM cells by recently activated T cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Iborra, S. et al. Optimal generation of tissue-resident but not circulating memory T cells during viral infection requires crosspriming by DNGR-1+ dendritic cells. Immunity 45, 847–860 (2016). This work demonstrates that priming of naïve T cells by BATF3+ dendritic cells selectively allows the formation of TRM cells in skin and lung tissue in mouse models, and that this process is dependent on IL-15, IL-12 and CD24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Kim, T. S., Gorski, S. A., Hahn, S., Murphy, K. M. & Braciale, T. J. Distinct dendritic cell subsets dictate the fate decision between effector and memory CD8+ T cell differentiation by a CD24-dependent mechanism. Immunity 40, 400–413 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Mani, V. et al. Migratory DCs activate TGF-β to precondition naïve CD8+ T cells for tissue-resident memory fate. Science 366, eaav5728 (2019). This work demonstrates that under steady-state conditions, TGFβ activated by dendritic cells epigenetically conditions naive T cells, which in turn allows naive T cells to develop into TRM cells when responding to infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Zaid, A. et al. Chemokine receptor-dependent control of skin tissue-resident memory T cell formation. J. Immunol. 199, 2451–2459 (2017).

    Article  CAS  PubMed  Google Scholar 

  84. Wein, A. N. et al. CXCR6 regulates localization of tissue-resident memory CD8 T cells to the airways. J. Exp. Med. 216, 2748–2762 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Ma, C., Mishra, S., Demel, E. L., Liu, Y. & Zhang, N. TGF-β controls the formation of kidney-resident T cells via promoting effector T cell extravasation. J. Immunol. 198, 749–756 (2017).

    Article  CAS  PubMed  Google Scholar 

  86. Sanjabi, S., Mosaheb, M. M. & Flavell, R. A. Opposing effects of TGF-β and IL-15 cytokines control the number of short-lived effector CD8+ T cells. Immunity 31, 131–144 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Cammack, A. J. et al. A viral toolkit for recording transcription factor–DNA interactions in live mouse tissues. Proc. Natl Acad. Sci. USA 117, 10003–10014 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Tu, E. et al. T cell receptor-regulated TGF-β type I receptor expression determines T cell quiescence and activation. Immunity 48, 745–759.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Borges da Silva, H. et al. Sensing of ATP via the purinergic receptor P2RX7 promotes CD8+ TRM cell generation by enhancing their sensitivity to the cytokine TGF-β. Immunity 53, 158–171.e6 (2020). This work, through the use of a P2rx7-deficient mouse model, shows that P2RX7 is required for TGFβ receptor expression by effector T cells, which in turn is essential to allow formation of TRM cell precursors and mature TRM cells.

    Article  CAS  PubMed  Google Scholar 

  90. Borges da Silva, H. et al. The purinergic receptor P2RX7 directs metabolic fitness of long-lived memory CD8+ T cells. Nature 559, 264–268 (2018).

    Article  CAS  PubMed  Google Scholar 

  91. Stark, R. et al. TRM maintenance is regulated by tissue damage via P2RX7. Sci. Immunol. 3, eaau1022 (2018).

    Article  PubMed  Google Scholar 

  92. Bromley, S. K. et al. CD49a regulates cutaneous resident memory CD8+ T cell persistence and response. Cell Rep. 32, 108085 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Reilly, E. C. et al. T RM integrins CD103 and CD49a differentially support adherence and motility after resolution of influenza virus infection. Proc. Natl Acad. Sci. USA 117, 12306–12314 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Rao, R. R., Li, Q., Odunsi, K. & Shrikant, P. A. The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and eomesodermin. Immunity 32, 67–78 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Sowell, R. T. et al. IL-15 complexes induce migration of resting memory CD8 T cells into mucosal tissues. J. Immunol. 199, 2536–2546 (2017).

    Article  CAS  PubMed  Google Scholar 

  96. Sowell, R. T., Rogozinska, M., Nelson, C. E., Vezys, V. & Marzo, A. L. Cutting Edge: generation of effector cells that localize to mucosal tissues and form resident memory CD8 T cells is controlled by mTOR. J. Immunol. 193, 2067–2071 (2014).

    Article  CAS  PubMed  Google Scholar 

  97. Zhou, A. C., Batista, N. V. & Watts, T. H. 4-1BB regulates effector CD8 T cell accumulation in the lung tissue through a TRAF1-, mTOR-, and antigen-dependent mechanism to enhance tissue-resident memory T cell formation during respiratory influenza infection. J. Immunol. 202, 2482–2492 (2019).

    Article  CAS  PubMed  Google Scholar 

  98. Pollizzi, K. N. et al. Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8+ T cell differentiation. Nat. Immunol. 17, 704–711 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Joshi, N. S. et al. Inflammation directs memory precursor and short-lived effector CD8+ T cell fates via the graded expression of T-bet transcription factor. Immunity 27, 281–295 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Laidlaw, B. J. et al. Production of IL-10 by CD4+ regulatory T cells during the resolution of infection promotes the maturation of memory CD8+ T cells. Nat. Immunol. 16, 871–879 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Gebhardt, T. et al. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 477, 216–219 (2011).

    Article  CAS  PubMed  Google Scholar 

  102. Mora, J. R. et al. Selective imprinting of gut-homing T cells by Peyer’s patch dendritic cells. Nature 424, 88–93 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Campbell, D. J. & Butcher, E. C. Rapid acquisition of tissue-specific homing phenotypes by CD4+ T cells activated in cutaneous or mucosal lymphoid tissues. J. Exp. Med. 195, 135–141 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Sigmundsdottir, H. et al. DCs metabolize sunlight-induced vitamin D3 to ‘program’ T cell attraction to the epidermal chemokine CCL27. Nat. Immunol. 8, 285–293 (2007).

    Article  CAS  PubMed  Google Scholar 

  105. Cassani, B. et al. Gut-tropic T cells that express integrin α4β7 and CCR9 are required for induction of oral immune tolerance in mice. Gastroenterology 141, 2109–2118 (2011).

    Article  CAS  PubMed  Google Scholar 

  106. Iwata, M. et al. Retinoic acid imprints gut-homing specificity on T cells. Immunity 21, 527–538 (2004).

    Article  CAS  PubMed  Google Scholar 

  107. Wakim, L. M. et al. The molecular signature of tissue resident memory CD8 T cells isolated from the Brain. J. Immunol. 189, 3462–3471 (2012).

    Article  CAS  PubMed  Google Scholar 

  108. Intlekofer, A. M. et al. Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin. Nat. Immunol. 6, 1236–1244 (2005).

    Article  CAS  PubMed  Google Scholar 

  109. Laidlaw, B. J. et al. CD4+ T cell help guides formation of CD103+ lung-resident memory CD8+ T cells during influenza viral infection. Immunity 41, 633–645 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Zens, K. D. et al. Reduced generation of lung tissue-resident memory T cells during infancy. J. Exp. Med. 214, 2915–2932 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Banerjee, A. et al. Cutting Edge: the transcription factor eomesodermin enables CD8+ T cells to compete for the memory cell niche. J. Immunol. 185, 4988–4992 (2010).

    Article  CAS  PubMed  Google Scholar 

  112. Lin, W.-H. W. et al. CD8+ T lymphocyte self-renewal during effector cell determination. Cell Rep. 17, 1773–1782 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Utzschneider, D. T. et al. Early precursor T cells establish and propagate T cell exhaustion in chronic infection. Nat. Immunol. 21, 1256–1266 (2020).

    Article  CAS  PubMed  Google Scholar 

  114. Yao, C. et al. Single-cell RNA-seq reveals TOX as a key regulator of CD8+ T cell persistence in chronic infection. Nat. Immunol. 20, 890–901 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Wu, J. et al. T cell factor 1 suppresses CD103+ lung tissue-resident memory T cell development. Cell Rep. 31, 107484 (2020).

    Article  CAS  PubMed  Google Scholar 

  116. Danilo, M., Chennupati, V., Silva, J. G., Siegert, S. & Held, W. Suppression of Tcf1 by inflammatory cytokines facilitates effector CD8 T cell differentiation. Cell Rep. 22, 2107–2117 (2018).

    Article  CAS  PubMed  Google Scholar 

  117. Takemoto, N., Intlekofer, A. M., Northrup, J. T., Wherry, E. J. & Reiner, S. L. Cutting Edge: IL-12 inversely regulates T-bet and eomesodermin expression during pathogen-induced CD8+ T cell differentiation. J. Immunol. 177, 7515–7519 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Ren, X. et al. COVID-19 immune features revealed by a large-scale single-cell transcriptome atlas. Cell 184, 1895–1913.e19 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Mathew, D. et al. Deep immune profiling of COVID-19 patients reveals distinct immunotypes with therapeutic implications. Science 369, eabc8511 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Szabo, P. A. et al. Longitudinal profiling of respiratory and systemic immune responses reveals myeloid cell-driven lung inflammation in severe COVID-19. Immunity 54, 797–814.e6 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Wang, D. et al. The transcription factor Runx3 establishes chromatin accessibility of cis-regulatory landscapes that drive memory cytotoxic T lymphocyte formation. Immunity 48, 659–674.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Kragten, N. A. M. et al. Blimp-1 induces and Hobit maintains the cytotoxic mediator granzyme B in CD8 T cells. Eur. J. Immunol. 48, 1644–1662 (2018).

    Article  CAS  PubMed  Google Scholar 

  123. Xin, A. et al. A molecular threshold for effector CD8+ T cell differentiation controlled by transcription factors Blimp-1 and T-bet. Nat. Immunol. 17, 422–432 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Behr, F. M. et al. Tissue-resident memory CD8+ T cells shape local and systemic secondary T cell responses. Nat. Immunol. 21, 1070–1081 (2020). This work, through the development and application of a genomic tool that allows the long-term tracking of cells that previously expressed the mouse TRM cell-associated transcription factor HOBIT, finds that mouse TRM cells can egress from tissues to join the circulation.

    Article  CAS  PubMed  Google Scholar 

  125. Vieira Braga, F. A. et al. Blimp-1 homolog Hobit identifies effector-type lymphocytes in humans. Eur. J. Immunol. 45, 2945–2958 (2015).

    Article  CAS  PubMed  Google Scholar 

  126. Oja, A. E. et al. The transcription factor hobit identifies human cytotoxic CD4+ T cells. Front. Immunol. 8, 325 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Nicolet, B. P. et al. CD29 identifies IFN-γ-producing human CD8+ T cells with an increased cytotoxic potential. Proc. Natl Acad. Sci. USA 117, 6686–6696 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Kumar, B. V. et al. Human tissue-resident memory T cells are defined by core transcriptional and functional signatures in lymphoid and mucosal sites. Cell Rep. 20, 2921–2934 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Li, C. et al. The transcription factor Bhlhe40 programs mitochondrial regulation of resident CD8+ T cell fitness and functionality. Immunity 51, 491–507.e7 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Boddupalli, C. S. et al. ABC transporters and NR4A1 identify a quiescent subset of tissue-resident memory T cells. J. Clin. Invest. 126, 3905–3916 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  131. Nowyhed, H. N., Huynh, T. R., Thomas, G. D., Blatchley, A. & Hedrick, C. C. Cutting edge: the orphan nuclear receptor Nr4a1 regulates CD8+ T cell expansion and effector function through direct repression of Irf4. J. Immunol. 195, 3515–3519 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Liebmann, M. et al. Nur77 serves as a molecular brake of the metabolic switch during T cell activation to restrict autoimmunity. Proc. Natl Acad. Sci. USA 115, E8017–E8026 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Liu, X. et al. Genome-wide analysis identifies NR4A1 as a key mediator of T cell dysfunction. Nature 567, 525–529 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Lin, C.-C. et al. Bhlhe40 controls cytokine production by T cells and is essential for pathogenicity in autoimmune neuroinflammation. Nat. Commun. 5, 3551 (2014).

    Article  PubMed  CAS  Google Scholar 

  135. Yu, F. et al. The transcription factor Bhlhe40 is a switch of inflammatory versus antiinflammatory TH1 cell fate determination. J. Exp. Med. 215, 1813–1821 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Beura, L. K. et al. Intravital mucosal imaging of CD8+ resident memory T cells shows tissue-autonomous recall responses that amplify secondary memory. Nat. Immunol. 19, 173–182 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Park, S. L. et al. Local proliferation maintains a stable pool of tissue-resident memory T cells after antiviral recall responses. Nat. Immunol. 19, 183–191 (2018).

    Article  CAS  PubMed  Google Scholar 

  138. Stolley, J. M. et al. Retrograde migration supplies resident memory T cells to lung-draining LN after influenza infection. J. Exp. Med. 217, e20192197 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Klicznik, M. M. et al. Human CD4+CD103+ cutaneous resident memory T cells are found in the circulation of healthy individuals. Sci. Immunol. 4, eaav8995 (2019). This work describes the existence of CD4+ T cells in the blood of human subjects that transcriptionally resemble TRM cells, and through the use of xenograft models this study furthermore shows that human CD4+ TRM cells can re-enter the circulation and, subsequently, reseed distant skin sites as TRM cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Low, J. S. et al. Tissue-resident memory T cell reactivation by diverse antigen-presenting cells imparts distinct functional responses. J. Exp. Med. 217, e20192291 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Li, C. et al. TCR transgenic mice reveal stepwise, multi-site acquisition of the distinctive Fat-Treg phenotype. Cell 174, 285–299.e12 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Miragaia, R. J. et al. Single-cell transcriptomics of regulatory T cells reveals trajectories of tissue adaptation. Immunity 50, 493–504.e7 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Delacher, M. et al. Precursors for nonlymphoid-tissue treg cells reside in secondary lymphoid organs and are programmed by the transcription factor BATF. Immunity 52, 295–312.e11 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Masopust, D. & Schenkel, J. M. The integration of T cell migration, differentiation and function. Nat. Rev. Immunol. 13, 309–320 (2013).

    Article  CAS  PubMed  Google Scholar 

  145. Sheth, R. U. & Wang, H. H. DNA-based memory devices for recording cellular events. Nat. Rev. Genet. 19, 718–732 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    Lianne Kok & Ton N. Schumacher

  2. Department of Microbiology and Immunology, Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA

    David Masopust

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  1. Lianne Kok
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  2. David Masopust
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Contributions

L.K. researched data for the article. L.K. and T.N.M. discussed content and wrote the initial concept. L.K., D.M. and T.N.M. reviewed and edited the manuscript.

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Correspondence to Ton N. Schumacher.

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Nature Reviews Immunology thanks Benjamin A. Youngblood and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Glossary

CD8+ central memory T cells

(CD8+ TCM cells). CD8+ memory T cells with a high degree of proliferative potential upon reactivation, commonly identified by the expression of lymphoid homing marker CD62L, and that can be abundantly found in the spleen, blood and lymph nodes.

CD8+ effector memory T cells

(CD8+ TEM cells). CD8+ memory T cells with a high degree of cytotoxicity upon reactivation, which are commonly identified by the lack of CD62L expression, and that can be abundantly found in the spleen and blood.

CD8+ circulating memory T cells

(CD8+ TCIRCM cells). A collective term for all of the CD8+ memory T cells that can circulate through the body and that are predominantly found in the blood, spleen and lymph nodes; the TCIRCM cell population encompasses both the CD8+ central memory T cell (TCM cell) and the CD8+ effector memory T cell (TEM cell) lineages.

CD8+ tissue resident memory T cells

(CD8+ TRM cells). CD8+ memory T cells that, under steady-state conditions, are consistently excluded from the circulation and reside in tissues; TRM cells in mucosal tissue, such as the lung, gut and skin, are typically identified as CD103+CD69+.

CD8+ effector-stage T cells

(CD8+ TEFF cells). All activated CD8+ T cells present around the peak of the expansion phase elicited by infection or vaccination, regardless of phenotype or function.

Lymphoid tissues

A collective term for the thymus, bone marrow, lymph nodes and spleen; in this Review, this term predominantly refers to spleen and lymph nodes.

Fate conditioning/poising

Enhancing the intrinsic capacity of a cell to give rise to a particular cell lineage through the induction of epigenetic and/or transcriptional changes.

TRM cell-poised state

A state that skews the differentiation potential of T cells towards the tissue resident memory T cell (TRM cell) lineage.

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Kok, L., Masopust, D. & Schumacher, T.N. The precursors of CD8+ tissue resident memory T cells: from lymphoid organs to infected tissues. Nat Rev Immunol 22, 283–293 (2022). https://doi.org/10.1038/s41577-021-00590-3

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