Self and Microbiota-derived Epitopes Induce CD4 T Cell Anergy and Conversion into CD4Foxp3 Regulatory Cells

Overview

Journal Mucosal Immunol

Publisher Elsevier

Specialty Allergy & Immunology

Date 2020 Nov 3

PMID 33139845

Citations 15

Authors

Michal P Kuczma

Edyta A Szurek

Anna Cebula

Vu L Ngo

Maciej Pietrzak

Piotr Kraj

Timothy L Denning

Leszek Ignatowicz

Affiliations

Soon will be listed here.

Abstract

The physiological role of T cell anergy induction as a key mechanism supporting self-tolerance remains undefined, and natural antigens that induce anergy are largely unknown. In this report, we used TCR sequencing to show that the recruitment of CD4CD44Foxp3CD73FR4 anergic (Tan) cells expands the CD4Foxp3 (Tregs) repertoire. Next, we report that blockade in peripherally-induced Tregs (pTregs) formation due to mutation in CNS1 region of Foxp3 or chronic exposure to a selecting self-peptide result in an accumulation of Tan cells. Finally, we show that microbial antigens from Akkermansia muciniphila commensal bacteria can induce anergy and drive conversion of naive CD4CD44Foxp3 T (Tn) cells to the Treg lineage. Overall, data presented here suggest that Tan induction helps the Treg repertoire to become optimally balanced to provide tolerance toward ubiquitous and microbiome-derived epitopes, improving host ability to avert systemic autoimmunity and intestinal inflammation.

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References

Schwartz R . T cell clonal anergy. Curr Opin Immunol. 1997; 9(3):351-7. DOI: 10.1016/s0952-7915(97)80081-7. View

Ermann J, Szanya V, Ford G, Paragas V, Fathman C, Lejon K . CD4(+)CD25(+) T cells facilitate the induction of T cell anergy. J Immunol. 2001; 167(8):4271-5. DOI: 10.4049/jimmunol.167.8.4271. View

Crespo J, Sun H, Welling T, Tian Z, Zou W . T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr Opin Immunol. 2013; 25(2):214-21. PMC: 3636159. DOI: 10.1016/j.coi.2012.12.003. View

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

Martinez R, Zhang N, Thomas S, Nandiwada S, Jenkins M, Binstadt B . Arthritogenic self-reactive CD4+ T cells acquire an FR4hiCD73hi anergic state in the presence of Foxp3+ regulatory T cells. J Immunol. 2011; 188(1):170-81. PMC: 3244540. DOI: 10.4049/jimmunol.1101311. View

Chappert P, Schwartz R . Induction of T cell anergy: integration of environmental cues and infectious tolerance. Curr Opin Immunol. 2010; 22(5):552-9. PMC: 2981408. DOI: 10.1016/j.coi.2010.08.005. View

Pauken K, Linehan J, Spanier J, Sahli N, Kalekar L, Binstadt B . Cutting edge: type 1 diabetes occurs despite robust anergy among endogenous insulin-specific CD4 T cells in NOD mice. J Immunol. 2013; 191(10):4913-7. PMC: 3987747. DOI: 10.4049/jimmunol.1301927. View

Stuller K, Ding H, Redline R, Czinn S, Blanchard T . CD25+ T cells induce Helicobacter pylori-specific CD25- T-cell anergy but are not required to maintain persistent hyporesponsiveness. Eur J Immunol. 2008; 38(12):3426-35. PMC: 2753502. DOI: 10.1002/eji.200838428. View

Kalekar L, Mueller D . Relationship between CD4 Regulatory T Cells and Anergy In Vivo. J Immunol. 2017; 198(7):2527-2533. PMC: 5363282. DOI: 10.4049/jimmunol.1602031. View

10.

Pacholczyk R, Ignatowicz H, Kraj P, Ignatowicz L . Origin and T cell receptor diversity of Foxp3+CD4+CD25+ T cells. Immunity. 2006; 25(2):249-59. DOI: 10.1016/j.immuni.2006.05.016. View

11.

Cebula A, Seweryn M, Rempala G, Pabla S, McIndoe R, Denning T . Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota. Nature. 2013; 497(7448):258-62. PMC: 3711137. DOI: 10.1038/nature12079. View

12.

Tuncel J, Benoist C, Mathis D . T cell anergy in perinatal mice is promoted by T reg cells and prevented by IL-33. J Exp Med. 2019; 216(6):1328-1344. PMC: 6547863. DOI: 10.1084/jem.20182002. View

13.

Ramsdell F . Foxp3 and natural regulatory T cells: key to a cell lineage?. Immunity. 2003; 19(2):165-8. DOI: 10.1016/s1074-7613(03)00207-3. View

14.

Shevach E, McHugh R, Piccirillo C, Thornton A . Control of T-cell activation by CD4+ CD25+ suppressor T cells. Immunol Rev. 2001; 182:58-67. DOI: 10.1034/j.1600-065x.2001.1820104.x. View

15.

Park H, Paik D, Jang E, Hong S, Youn J . Acquisition of anergic and suppressive activities in transforming growth factor-beta-costimulated CD4+CD25- T cells. Int Immunol. 2004; 16(8):1203-13. DOI: 10.1093/intimm/dxh123. View

16.

Schmidt A, Oberle N, Krammer P . Molecular mechanisms of treg-mediated T cell suppression. Front Immunol. 2012; 3:51. PMC: 3341960. DOI: 10.3389/fimmu.2012.00051. View

17.

Feng T, Wang L, Schoeb T, Elson C, Cong Y . Microbiota innate stimulation is a prerequisite for T cell spontaneous proliferation and induction of experimental colitis. J Exp Med. 2010; 207(6):1321-32. PMC: 2882839. DOI: 10.1084/jem.20092253. View

18.

Wojciech L, Ignatowicz A, Seweryn M, Rempala G, Pabla S, McIndoe R . The same self-peptide selects conventional and regulatory CD4⁺ T cells with identical antigen receptors. Nat Commun. 2014; 5:5061. PMC: 4183978. DOI: 10.1038/ncomms6061. View

19.

Sharabi A, Tsokos M, Ding Y, Malek T, Klatzmann D, Tsokos G . Regulatory T cells in the treatment of disease. Nat Rev Drug Discov. 2018; 17(11):823-844. DOI: 10.1038/nrd.2018.148. View

20.

Kuczma M, Szurek E, Cebula A, Chassaing B, Jung Y, Kang S . Commensal epitopes drive differentiation of colonic T. Sci Adv. 2020; 6(16):eaaz3186. PMC: 7164940. DOI: 10.1126/sciadv.aaz3186. View