Insulin-reactive T cells convert diabetogenic insulin-reactive VH125 B cells into tolerogenic cells by reducing germinal center T:B cell Interactions in NOD mice

Pearson, James A. ORCID: https://orcid.org/0000-0002-2867-2269, Li, Yangyang, Majewska-Szczepanik, Monika, Guo, Junhua, Zhang, Li, Liu, Yu, Wong, F. Susan ORCID: https://orcid.org/0000-0002-2812-8845 and Wen, Li 2020. Insulin-reactive T cells convert diabetogenic insulin-reactive VH125 B cells into tolerogenic cells by reducing germinal center T:B cell Interactions in NOD mice. Frontiers in Immunology 11 , 585886. 10.3389/fimmu.2020.585886

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Abstract

Insulin is a key autoantigen in Type 1 Diabetes (T1D), targeted by both T and B cells. Therefore, understanding insulin-specific T:B cell interactions is important. We have previously reported an insulin-reactive CD4+ T cell, (designated 2H6). Unlike other insulin-reactive T cells, 2H6 cells protect non-obese diabetic (NOD) mice from T1D development, mediated by TGFβ. To investigate insulin-specific T:B cell interactions, we bred 2H6αβ T cell receptor transgenic NOD mice (2H6) with the insulin-reactive B cell receptor transgenic NOD mice (VH125), generating 2H6VH125 NOD mice. Similar to 2H6 mice, 2H6VH125 mice are protected from T1D development. Interestingly, VH125 B cells did not alter the phenotype of 2H6 T cells; however, 2H6 T cells significantly altered the VH125 B cells by reducing the insulin-reactive non-germinal center (GC) and GC B cells, as well as MHC and costimulatory molecule expression on the B cells. Furthermore, the B cells in 2H6VH125 NOD mice exhibited increased non-insulin-specific and a class switched IgG isotype, which can be recapitulated in vivo in Rag-deficient NOD mice by adoptive transfer. In vitro, VH125 B cells from 2H6VH125 mice suppressed the proliferation of 2H6 T cells to insulin antigen but enhanced TGFβ secretion by 2H6 T cells from 2H6VH125 mice compared to 2H6 mice. In summary, our data showed that 2H6 CD4+ T cells alter the phenotype and function of insulin-reactive B cells from pathogenic to tolerogenic cells. In turn, VH125 B cells also modulate the function of the 2H6 T cells. Thus, promoting the interactions between antigen-specific regulatory T cells and B cells may lead to protection from T1D.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Publisher:	Frontiers Media
ISSN:	1664-3224
Funders:	MRC
Date of First Compliant Deposit:	4 December 2020
Date of Acceptance:	16 October 2020
Last Modified:	05 May 2023 11:11
URI:	https://orca.cardiff.ac.uk/id/eprint/136795

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