Pre-Germinal Center Interactions with T Cells Are Natural Checkpoints to Limit Autoimmune B Cell Responses [IMMUNE REGULATION]

Key Points

Interactions between myelin Ag-specific T and B cells are of low quality.

Autoimmune B cells express low levels of molecules to support T cell interactions.

Myelin Ag-specific B cells are inherently less responsive to BCR stimulation.

Abstract

Interactions with Ag-specific T cells drive B cell activation and fate choices that ultimately determine the quality of high-affinity Ab responses. As such, these interactions, and especially the long-lived interactions that occur before germinal center formation, may be important checkpoints to regulate undesirable responses. Using mouse model Ag systems, we directly observed interactions between T and B cells responding to the self-antigen myelin oligodendrocyte glycoprotein (MOG) and found that they are of lower quality compared with interactions between cells responding to the model foreign Ag nitrophenyl-haptenated OVA. This was associated with reduced expression of molecules that facilitate these interactions on the B cells, but not on T cells. B cell expression of these molecules was not dictated by the T cell partner, nor could the relative lack of expression on MOG-specific (MOG-sp.) B cells be reversed by a multivalent Ag. Instead, MOG-sp. B cells were inherently less responsive to BCR stimulation than MOG-non-sp. cells. However, the phenotype of MOG-sp. B cells was not consistent with previous descriptions of autoimmune B cells that had been tolerized via regular exposure to systemically expressed self-antigen. This suggests that alternate anergy pathways may exist to limit B cell responses to tissue-restricted self-antigens.

Footnotes

This work was supported by a Discovery Grant from the National Sciences and Engineering Council of Canada (NSERC) and a Discovery Research Operating Grant from the Multiple Sclerosis Society of Canada (MSSOC). K.A.P. is the recipient of an endMS Post-Doctoral Fellowship from the MSSOC. X.X.S.T. was a recipient of an NSERC Undergraduate Summer Research Award.

The online version of this article contains supplemental material.

Abbreviations used in this article:

Ag-sp.Ag-specificEAEexperimental autoimmune encephalomyelitisGCgerminal centerICOSinducible T Cell costimulatorICOSLligand for T cell ICOSMOGmyelin oligodendrocyte glycoproteinMOG-sp.MOG-specificMSmultiple sclerosisNP-OVAnitrophenyl-haptenated OVATfhT follicular helperReceived July 25, 2022.Accepted August 25, 2022.Copyright © 2022 by The American Association of Immunologists, Inc.

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