The Endogenous Repertoire Harbors Self-reactive CD4 T Cell Clones That Adopt a Follicular Helper T Cell-like Phenotype at Steady State

Overview

Journal Nat Immunol

Date 2023 Feb 9

PMID 36759711

Authors

Victoria Lee

Donald M Rodriguez

Nicole K Ganci

Sharon Zeng

Junting Ai

Jaime L Chao

Matthew T Walker

Christine H Miller

David E J Klawon

Mary H Schoenbach

Domenick E Kennedy

Mark Maienschein-Cline

Nicholas D Socci

Marcus R Clark

Peter A Savage

Affiliations

Soon will be listed here.

Abstract

The T cell repertoire of healthy mice and humans harbors self-reactive CD4 conventional T (T) cells capable of inducing autoimmunity. Using T cell receptor profiling paired with in vivo clonal analysis of T cell differentiation, we identified T cell clones that are recurrently enriched in non-lymphoid organs following ablation of Foxp3 regulatory T (T) cells. A subset of these clones was highly proliferative in the lymphoid organs at steady state and exhibited overt reactivity to self-ligands displayed by dendritic cells, yet were not purged by clonal deletion. These clones spontaneously adopted numerous hallmarks of follicular helper T (T) cells, including expression of Bcl6 and PD-1, exhibited an elevated propensity to localize within B cell follicles at steady state, and produced interferon-γ in non-lymphoid organs following sustained T cell depletion. Our work identifies a naturally occurring population of self-reactive T-like cells and delineates a previously unappreciated fate for self-specific T cells.

Citing Articles

Microbiome Differences in Colorectal Cancer Patients and Healthy Individuals: Implications for Vaccine Antigen Discovery.

Ibeanu G, Rowaiye A, Okoli J, Eze D Immunotargets Ther. 2024; 13:749-774.

PMID: 39698218 PMC: 11652712. DOI: 10.2147/ITT.S486731.

Help me help you: emerging concepts in T follicular helper cell differentiation, identity, and function.

Wellford S, Schwartzberg P Curr Opin Immunol. 2024; 87:102421.

PMID: 38733669 PMC: 11482284. DOI: 10.1016/j.coi.2024.102421.

CARD11 regulates the thymic Treg development in an NF-κB-independent manner.

Hu Y, Han L, Xu W, Li T, Zhao Q, Lu W Front Immunol. 2024; 15:1364957.

PMID: 38650932 PMC: 11033321. DOI: 10.3389/fimmu.2024.1364957.

T cell help shapes B cell tolerance.

Akama-Garren E, Yin X, Prestwood T, Ma M, Utz P, Carroll M Sci Immunol. 2024; 9(92):eadj7029.

PMID: 38363829 PMC: 11095409. DOI: 10.1126/sciimmunol.adj7029.

Lineage origin and transcriptional control of autoantigen-specific T-regulatory type 1 cells.

Angelats E, Santamaria P Front Immunol. 2023; 14:1267697.

PMID: 37818381 PMC: 10560755. DOI: 10.3389/fimmu.2023.1267697.

References

Klein L, Kyewski B, Allen P, Hogquist K . Positive and negative selection of the T cell repertoire: what thymocytes see (and don't see). Nat Rev Immunol. 2014; 14(6):377-91. PMC: 4757912. DOI: 10.1038/nri3667. View

Hogquist K, Jameson S . The self-obsession of T cells: how TCR signaling thresholds affect fate 'decisions' and effector function. Nat Immunol. 2014; 15(9):815-23. PMC: 4348363. DOI: 10.1038/ni.2938. View

Bouneaud C, Kourilsky P, Bousso P . Impact of negative selection on the T cell repertoire reactive to a self-peptide: a large fraction of T cell clones escapes clonal deletion. Immunity. 2001; 13(6):829-40. DOI: 10.1016/s1074-7613(00)00080-7. View

Zehn D, Bevan M . T cells with low avidity for a tissue-restricted antigen routinely evade central and peripheral tolerance and cause autoimmunity. Immunity. 2006; 25(2):261-70. PMC: 2774714. DOI: 10.1016/j.immuni.2006.06.009. View

Yu W, Jiang N, Ebert P, Kidd B, Muller S, Lund P . Clonal Deletion Prunes but Does Not Eliminate Self-Specific αβ CD8(+) T Lymphocytes. Immunity. 2015; 42(5):929-41. PMC: 4455602. DOI: 10.1016/j.immuni.2015.05.001. View

Kim J, Rasmussen J, Rudensky A . Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat Immunol. 2006; 8(2):191-7. DOI: 10.1038/ni1428. View

Lahl K, Loddenkemper C, Drouin C, Freyer J, Arnason J, Eberl G . Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J Exp Med. 2007; 204(1):57-63. PMC: 2118432. DOI: 10.1084/jem.20061852. View

Chinen T, Volchkov P, Chervonsky A, Rudensky A . A critical role for regulatory T cell-mediated control of inflammation in the absence of commensal microbiota. J Exp Med. 2010; 207(11):2323-30. PMC: 2964571. DOI: 10.1084/jem.20101235. View

Yi J, Jung J, Hong S, Lee J, Han D, Kim K . Unregulated antigen-presenting cell activation by T cells breaks self tolerance. Proc Natl Acad Sci U S A. 2019; 116(3):1007-1016. PMC: 6338877. DOI: 10.1073/pnas.1818624116. View

10.

Fernando M, Stevens C, Walsh E, De Jager P, Goyette P, Plenge R . Defining the role of the MHC in autoimmunity: a review and pooled analysis. PLoS Genet. 2008; 4(4):e1000024. PMC: 2291482. DOI: 10.1371/journal.pgen.1000024. View

11.

Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M . Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol. 1995; 155(3):1151-64. View

12.

Morrissey P, Charrier K, Braddy S, Liggitt D, Watson J . CD4+ T cells that express high levels of CD45RB induce wasting disease when transferred into congenic severe combined immunodeficient mice. Disease development is prevented by cotransfer of purified CD4+ T cells. J Exp Med. 1993; 178(1):237-44. PMC: 2191069. DOI: 10.1084/jem.178.1.237. View

13.

Powrie F, Leach M, Mauze S, Caddle L, Coffman R . Phenotypically distinct subsets of CD4+ T cells induce or protect from chronic intestinal inflammation in C. B-17 scid mice. Int Immunol. 1993; 5(11):1461-71. DOI: 10.1093/intimm/5.11.1461. View

14.

Kim H, Verbinnen B, Tang X, Lu L, Cantor H . Inhibition of follicular T-helper cells by CD8(+) regulatory T cells is essential for self tolerance. Nature. 2010; 467(7313):328-32. PMC: 3395240. DOI: 10.1038/nature09370. View

15.

Richards D, Ruggiero E, Hofer A, Sefrin J, Schmidt M, von Kalle C . The Contained Self-Reactive Peripheral T Cell Repertoire: Size, Diversity, and Cellular Composition. J Immunol. 2015; 195(5):2067-79. DOI: 10.4049/jimmunol.1500880. View

16.

Kawabe T, Jankovic D, Kawabe S, Huang Y, Lee P, Yamane H . Memory-phenotype CD4 T cells spontaneously generated under steady-state conditions exert innate T1-like effector function. Sci Immunol. 2017; 2(12). PMC: 5568832. DOI: 10.1126/sciimmunol.aam9304. View

17.

Levine A, Mendoza A, Hemmers S, Moltedo B, Niec R, Schizas M . Stability and function of regulatory T cells expressing the transcription factor T-bet. Nature. 2017; 546(7658):421-425. PMC: 5482236. DOI: 10.1038/nature22360. View

18.

Kawabe T, Yi J, Kawajiri A, Hilligan K, Fang D, Ishii N . Requirements for the differentiation of innate T-bet memory-phenotype CD4 T lymphocytes under steady state. Nat Commun. 2020; 11(1):3366. PMC: 7338451. DOI: 10.1038/s41467-020-17136-1. View

19.

Kalekar L, Schmiel S, Nandiwada S, Lam W, Barsness L, Zhang N . CD4(+) T cell anergy prevents autoimmunity and generates regulatory T cell precursors. Nat Immunol. 2016; 17(3):304-14. PMC: 4755884. DOI: 10.1038/ni.3331. View

20.

Malchow S, Leventhal D, Nishi S, Fischer B, Shen L, Paner G . Aire-dependent thymic development of tumor-associated regulatory T cells. Science. 2013; 339(6124):1219-24. PMC: 3622085. DOI: 10.1126/science.1233913. View