Abstract
Autoimmunity increases the risk of developing B lymphoma in humans; however, the molecular mechanism(s) underlying this link remain(s) unexplained. Here, we develop a mouse model to dissect the contribution of Id-driven T-B collaboration and show that chronic interaction between B cells and CD4+ T cells first leads to autoimmunity and later to the development of B (and T) cell lymphomas. We find that serum autoantibodies and lymphoma B cell receptor (BCR) are related and have the same specificity for ubiquitous self-antigens (histone and nucleosome) (Signal 1). Self-reactive B lymphoma cells are helped by CD4+ T cells that recognize a lymphoma neoantigen, an MHC class II-presented Idiotypic (Id) peptide (Signal 2). The mechanism, called Id-driven T-B collaboration, results in relentless mutual stimulation of B and T cells with germinal center markers, autoimmunity, and finally, malignant transformation of either B or T cells. Our results thus indicate Id-driven T-B collaboration as a potential mechanism linking autoimmunity and the development of lymphomas.
Data availability
The aligned lymphoma BCR sequences data generated in this study have been deposited in the Genbank database under accession code PV068692 - PV068753 [https://www.ncbi.nlm.nih.gov/nuccore/?term=VLambda2%2B%2F-+Id-sp+TCR-Tg%2B%2F-] and PV068754 - PV068825 [https://www.ncbi.nlm.nih.gov/nuccore/?term=Vlambda2315%2B%2F-+Id-sp.+TCR-TG%2B%2F-]. The mass spectrometry data from serum and recombinant Immunoglobulin data generated in this study have been deposited in Pride under Accession numberPXD063326 [https://www.ebi.ac.uk/pride/archive/projects/PXD063326]. All data are included in the supplementary section. The raw numbers for charts and graphs are available in the Source Data file. Source data are provided with this paper.
References
Pisetsky, D. S. Pathogenesis of autoimmune disease. Nat. Rev. Nephrol. 19, 509–524 (2023).
Lee, K. H. et al. Understanding the immunopathogenesis of autoimmune diseases by animal studies using gene modulation: a comprehensive review. Autoimmun. Rev. 19, 102469 (2020).
Shaffer, A. L. 3rd, Young, R. M. & Staudt, L. M. Pathogenesis of human B cell lymphomas. Annu Rev. Immunol. 30, 565–610 (2012).
Thurner, L. et al. Role of specific B-cell receptor antigens in lymphomagenesis. Front Oncol. 10, 604685 (2020).
Kleinstern, G. et al. History of autoimmune conditions and lymphoma prognosis. Blood Cancer J. 8, 73 (2018).
Ekstrom Smedby, K. et al. Autoimmune disorders and risk of non-Hodgkin lymphoma subtypes: a pooled analysis within the InterLymph Consortium. Blood 111, 4029–4038 (2008).
Baecklund, E., Smedby, K. E., Sutton, L. A., Askling, J. & Rosenquist, R. Lymphoma development in patients with autoimmune and inflammatory disorders-what are the driving forces? Semin. Cancer Biol. 24, 61–70 (2014).
Victora, G. D. & Nussenzweig, M. C. Germinal centers. Annu. Rev. Immunol. 40, 413–442 (2022).
Weiss, S. & Bogen, B. B-lymphoma cells process and present their endogenous immunoglobulin to major histocompatibility complex-restricted T cells. Proc. Natl. Acad. Sci. USA 86, 282–286 (1989).
Bogen, B. & Weiss, S. Processing and presentation of idiotypes to MHC-restricted T cells. Int. Rev. Immunol. 10, 337–355 (1993).
Lanzavecchia, A. Antigen-specific interaction between T and B cells. Nature 314, 537–539 (1985).
Munthe, L. A., Os, A., Zangani, M. & Bogen, B. MHC-restricted Ig V region-driven T-B lymphocyte collaboration: B cell receptor ligation facilitates switch to IgG production. J. Immunol. 172, 7476–7484 (2004).
Munthe, L. A., Corthay, A., Os, A., Zangani, M. & Bogen, B. Systemic autoimmune disease caused by autoreactive B cells that receive chronic help from Ig V region-specific T cells. J. Immunol. 175, 2391–2400 (2005).
Snyder, C. M. et al. Activation and tolerance in CD4(+) T cells reactive to an immunoglobulin variable region. J. Exp. Med. 200, 1–11 (2004).
Zangani, M. M. et al. Lymphomas can develop from B cells chronically helped by idiotype-specific T cells. J. Exp. Med. 204, 1181–1191 (2007).
Williams, W. M., Staines, N. A., Muller, S. & Isenberg, D. A. Human T cell responses to autoantibody variable region peptides. Lupus 4, 464–471 (1995).
van Schooten, W. C. et al. Joint-derived T cells in rheumatoid arthritis react with self-immunoglobulin heavy chains or immunoglobulin-binding proteins that copurify with immunoglobulin. Eur. J. Immunol. 24, 93–98 (1994).
Hestvik, A. L. et al. T cells from multiple sclerosis patients recognize multiple epitopes on Self-IgG. Scand. J. Immunol. 66, 393–401 (2007).
Os, A. et al. Chronic lymphocytic leukemia cells are activated and proliferate in response to specific T helper cells. Cell Rep. 4, 566–577 (2013).
Khodadoust, M. S. et al. Antigen presentation profiling reveals recognition of lymphoma immunoglobulin neoantigens. Nature 543, 723–727 (2017).
Khodadoust, M. S. et al. B-cell lymphomas present immunoglobulin neoantigens. Blood 133, 878–881 (2019).
Eyerman, M. C. & Wysocki, L. T cell recognition of somatically-generated Ab diversity. J. Immunol. 152, 1569–1577 (1994).
Eyerman, M. C., Zhang, X. & Wysocki, L. J. T cell recognition and tolerance of antibody diversity. J. Immunol. 157, 1037–1046 (1996).
Bogen, B., Jorgensen, T. & Hannestad, K. T helper cell recognition of idiotopes on lambda 2 light chains of M315 and T952: evidence for dependence on somatic mutations in the third hypervariable region. Eur. J. Immunol. 15, 278–281 (1985).
Guo, W., Smith, D., Guth, A., Aviszus, K. & Wysocki, L. J. T cell tolerance to germline-encoded antibody sequences in a lupus-prone mouse. J. Immunol. 175, 2184–2190 (2005).
Huszthy, P. C. et al. B cell receptor ligation induces display of V-region peptides on MHC class II molecules to T cells. Proc. Natl. Acad. Sci. USA 116, 25850–25859 (2019).
Bogen, B., Gleditsch, L., Weiss, S. & Dembic, Z. Weak positive selection of transgenic T cell receptor-bearing thymocytes: importance of major histocompatibility complex class II, T cell receptor and CD4 surface molecule densities. Eur. J. Immunol. 22, 703–709 (1992).
Crotty, S. T follicular helper cell differentiation, function, and roles in disease. Immunity 41, 529–542 (2014).
Bocharnikov, A. V. et al. PD-1hiCXCR5- T peripheral helper cells promote B cell responses in lupus via MAF and IL-21. JCI Insight 4 https://doi.org/10.1172/jci.insight.130062 (2019).
Del Carmen Crespo Oliva, C., Labrie, M. & Allard-Chamard, H. T peripheral helper (Tph) cells, a marker of immune activation in cancer and autoimmune disorders. Clin. Immunol. 266, 110325 (2024).
Spolski, R. & Leonard, W. J. IL-21 and T follicular helper cells. Int. Immunol. 22, 7–12 (2010).
Gupta, M. et al. Elevated serum IL-10 levels in diffuse large B-cell lymphoma: a mechanism of aberrant JAK2 activation. Blood 119, 2844–2853 (2012).
Morse, H. C. et al. Bethesda proposals for classification of lymphoid neoplasms in mice. Blood 100, 246–258 (2002).
Ree, H. J. et al. Coexpression of Bcl-6 and CD10 in diffuse large B-cell lymphomas: significance of Bcl-6 expression patterns in identifying germinal center B-cell lymphoma. Hum. Pathol. 32, 954–962 (2001).
Sainz, T. P. et al. Role of the crosstalk B:neoplastic T follicular helper cells in the pathobiology of nodal T follicular helper cell lymphomas. Lab Invest. 104, 102147 (2024).
Lees, W. IG receptor germline set for species: Mouse subgroup: BALB/c/ByJ set_name: BALB/c/ByJ IGLV (Version 2) [Data set]. 2 ed. Zenodo. https://zenodo.org/records/11002140 (2024).
Nemazee, D. Mechanisms of central tolerance for B cells. Nat. Rev. Immunol. 17, 281–294 (2017).
Sachen, K. L. et al. Self-antigen recognition by follicular lymphoma B-cell receptors. Blood 120, 4182–4190 (2012).
Cha, S. C. et al. Nonstereotyped lymphoma B cell receptors recognize vimentin as a shared autoantigen. J. Immunol. 190, 4887–4898 (2013).
Kramer, M. H. et al. Clinical relevance of BCL2, BCL6, and MYC rearrangements in diffuse large B-cell lymphoma. Blood 92, 3152–3162 (1998).
Lossos, I. S. et al. Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N. Engl. J. Med. 350, 1828–1837 (2004).
de Leval, L. et al. The gene expression profile of nodal peripheral T-cell lymphoma demonstrates a molecular link between angioimmunoblastic T-cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood 109, 4952–4963 (2007).
Piccaluga, P. P. et al. Gene expression analysis of angioimmunoblastic lymphoma indicates derivation from T follicular helper cells and vascular endothelial growth factor deregulation. Cancer Res. 67, 10703–10710 (2007).
Muller, S., Dieker, J., Tincani, A. & Meroni, P. L. Pathogenic anti-nucleosome antibodies. Lupus 17, 431–436 (2008).
Kuppers, R. Mechanisms of B-cell lymphoma pathogenesis. Nat. Rev. Cancer 5, 251–262 (2005).
Pasqualucci, L. & Dalla-Favera, R. Genetics of diffuse large B-cell lymphoma. Blood 131, 2307–2319 (2018).
Kridel, R., Sehn, L. H. & Gascoyne, R. D. Pathogenesis of follicular lymphoma. J. Clin. Invest. 122, 3424–3431 (2012).
Desai, M. K. & Brinton, R. D. Autoimmune disease in women: endocrine transition and risk across the lifespan. Front. Endocrinol. 10, 265 (2019).
Fraser, L. D. et al. Immunoglobulin light chain allelic inclusion in systemic lupus erythematosus. Eur. J. Immunol. 45, 2409–2419 (2015).
Peterson, J. N. et al. Elevated detection of dual antibody B cells identifies lupus patients with B cell-reactive VH4-34 autoantibodies. Front. Immunol. 13, 795209 (2022).
Yachimovich, N., Mostoslavsky, G., Yarkoni, Y., Verbovetski, I. & Eilat, D. The efficiency of B cell receptor (BCR) editing is dependent on BCR light chain rearrangement status. Eur. J. Immunol. 32, 1164–1174 (2002).
Pelanda, R. Dual immunoglobulin light chain B cells: Trojan horses of autoimmunity? Curr. Opin. Immunol. 27, 53–59 (2014).
Weiss, S. & Bogen, B. MHC class II-restricted presentation of intracellular antigen. Cell 64, 767–776 (1991).
Corthay, A. et al. Primary antitumor immune response mediated by CD4+ T cells. Immunity 22, 371–383 (2005).
Kruse, B. et al. CD4(+) T cell-induced inflammatory cell death controls immune-evasive tumours. Nature 618, 1033–1040 (2023).
Bawden, E. G. et al. CD4(+) T cell immunity against cutaneous melanoma encompasses multifaceted MHC II-dependent responses. Sci. Immunol. 9, eadi9517 (2024).
Chen, D. et al. CTLA-4 blockade induces a microglia-Th1 cell partnership that stimulates microglia phagocytosis and anti-tumor function in glioblastoma. Immunity 56, 2086–2104.e2088 (2023).
Wolf, S. P. et al. CD4(+) T cells with convergent TCR recombination reprogram stroma and halt tumor progression in adoptive therapy. Sci. Immunol. 9, eadp6529 (2024).
Miggelbrink, A. M. et al. CD4 T-cell exhaustion: does it exist and what are its roles in cancer? Clin. Cancer Res. 27, 5742–5752 (2021).
Pangault, C. et al. Follicular lymphoma cell niche: identification of a preeminent IL-4-dependent T(FH)-B cell axis. Leukemia 24, 2080–2089 (2010).
Mintz, M. A. & Cyster, J. G. T follicular helper cells in germinal center B cell selection and lymphomagenesis. Immunol. Rev. 296, 48–61 (2020).
Elliot, T. B., Carr, M., Eleni, L., Ahearne, M. & Wagner, S. Circulating Tfh1 (cTfh1) cell numbers and PD1 expression are elevated in low-grade B-cell non-Hodgkin’s lymphoma and cTfh gene expression is perturbed in marginal zone lymphoma. PLoS ONE 13 https://doi.org/10.1371/journal.pone.0190468 (2018).
Bogen, B., Lauritzsen, G. F. & Weiss, S. A stimulatory monoclonal antibody detecting T cell receptor diversity among idiotype-specific, major histocompatibility complex-restricted T cell clones. Eur. J. Immunol. 20, 2359–2362 (1990).
Bogen, B. Monoclonal antibodies specific for variable and constant domains of murine lambda chains. Scand. J. Immunol. 29, 273–279 (1989).
Berg, J., McDowell, M., Jack, H. M. & Wabl, M. Immunoglobulin lambda gene rearrangement can precede kappa gene rearrangement. Dev. Immunol. 1, 53–57 (1990).
Meyer, L. et al. A simplified workflow for monoclonal antibody sequencing. PLoS ONE 14, e0218717 (2019).
Kantor, A., Merrill, C. & Hillson, J. Construction of cDNA from single unstimulated mouse B lymphocytes: method and application to the study of expressed antibody repertoire in FACS-sorted murine B cell subsets. Blackwell Sci. 13, 1–6 (1996).
Tiller, T., Busse, C. E. & Wardemann, H. Cloning and expression of murine Ig genes from single B cells. J. Immunol. Methods 350, 183–193 (2009).
Chardes, T. et al. Efficient amplification and direct sequencing of mouse variable regions from any immunoglobulin gene family. FEBS Lett. 452, 386–394 (1999).
Bolotin, D. A. et al. MiXCR: software for comprehensive adaptive immunity profiling. Nat. Methods 12, 380–381 (2015).
Greiff, V. et al. Systems analysis reveals high genetic and antigen-driven predetermination of antibody repertoires throughout B cell development. Cell Rep. 19, 1467–1478 (2017).
Osorio, D., Rondón-Villarreal, P. & Torres Sáez, R. G. Peptides: a package for data mining of antimicrobial peptides. R J. 7, 4–14 (2015).
Norderhaug, L., Olafsen, T., Michaelsen, T. E. & Sandlie, I. Versatile vectors for transient and stable expression of recombinant antibody molecules in mammalian cells. J. Immunol. Methods 204, 77–87 (1997).
Buchner, C., Bryant, C., Eslami, A. & Lakos, G. Anti-nuclear antibody screening using HEp-2 cells. J. Vis. Exp. 88, e51211 (2014).
Acknowledgements
We would like to thank Peter Olaf Hofgaard and Hilde Omholt for their technical assistance. Thanks to Anders Tveita for his assistance in growing lymphoma cells in vitro. Ida Jonsson helped with viral transfection of NT34 lymphoma cell line with Effluc.GFP. We would like to thank the late Herbert C. Morse III for initiating the collaboration on lymphoma diagnosis. We acknowledge the staff of the Department of Comparative Medicine at Oslo University Hospital for their support and assistance with the animal housing facilities. We also acknowledge the proteomic core facility at Oslo University Hospital (supported by INFRASTRUKTUR-program (project number: 295910)) and Tuula Nyman and Sachin Singh for their help with mass spectrometry analysis. Prof. Oddmund Bakke is thanked for advice on confocal microscopy. We would also like to thank the following funding agencies: The Research Council of Norway: projects 221709 and 143073 (to BB); The Regional Health Authority (Helse Sør Øst): projects 40150 and 39921 (to BB).
Author information
Authors and Affiliations
Contributions
Designed experiments: R.P.G, P.C.H and B.B; performed experiments: R.P.G, P.C.H, J.M.W, V.G, R.B, X.H, L.B, K.L.Q, L.M. Analyzed experiments: All authors. Wrote the paper: R.P.G and B.B. Correspondence and material requests should be directed to Prof. Bjarne Bogen (bjarne.bogen@medisin.uio.no). All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Communications thanks the anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Source data
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Gopalakrishnan, R.P., Ward, J.M., Greiff, V. et al. Idiotype-specific CD4+ T cells chronically stimulate autoreactive B cells to develop into B lymphomas in mice. Nat Commun (2026). https://doi.org/10.1038/s41467-026-69916-w
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41467-026-69916-w
