The expansion in lymphoid organs of IL-4+ BATF+ T follicular helper cells is linked to IgG4 class switching in vivo.

Takashi Maehara,Takako Saeki,Shiv Pillai,Tamotsu Kiyoshima,Hidetaka Yamamoto,Samuel Jh Murphy,Noriko Ishiguro,Hamid Mattoo,Joe Daccache,Masaki Yamauchi,Grace J Yuen,Seiji Nakamura,Vinay S Mahajan,John H Stone,Masafumi Moriyama,Miho Ohta

doi:10.26508/lsa.201800050

Abstract

Distinct T follicular helper (TFH) subsets that influence specific class-switching events are assumed to exist, but the accumulation of isotype-specific TFH subsets in secondary lymphoid organs (SLOs) and tertiary lymphoid organs has not been hitherto demonstrated. IL-4-expressing TFH cells are surprisingly sparse in human SLOs. In contrast, in IgG4-related disease (IgG4-RD), a disorder characterized by polarized Ig class switching, most TFH cells in tertiary and SLOs make IL-4. Human IL-4+ TFH cells do not express GATA-3 but express nuclear BATF, and the transcriptomes of IL-4-secreting TFH cells differ from both PD1hi TFH cells that do not secrete IL-4 and IL-4-secreting non-TFH cells. Unlike IgG4-RD, IL-4+ TFH cells are rarely found in tertiary lymphoid organs in Sjögren's syndrome, a disorder in which IgG4 is not elevated. The proportion of CD4+IL-4+BATF+ T cells and CD4+IL-4+CXCR5+ T cells in IgG4-RD tissues correlates tightly with tissue IgG4 plasma cell numbers and plasma IgG4 levels in patients but not with the total plasma levels of other isotypes. These data describe a disease-related TFH subpopulation in human tertiary lymphoid organs and SLOs that is linked to IgG4 class switching.

Highlights

T follicular helper (TFH) cells provide help to B cells during T-dependent immune responses, and they contribute to isotype switching, somatic hypermutation, germinal center (GC) formation, and the selection of high-affinity B cells in the GC (Vinuesa et al, 2005; King et al, 2008; Crotty, 2011)
In T-dependent immune responses, it is widely accepted that specific cytokines induce the transcription of selected switch regions so that distinct Ig gene loci are targeted by activation-induced cytidine deaminase (AID) for the induction of cytidine deamination and double-strand break formation
We found that very few TFH cells in healthy tonsils or lymph nodes synthesize IL-4

Summary

Introduction

T follicular helper (TFH) cells provide help to B cells during T-dependent immune responses, and they contribute to isotype switching, somatic hypermutation, germinal center (GC) formation, and the selection of high-affinity B cells in the GC (Vinuesa et al, 2005; King et al, 2008; Crotty, 2011). How exactly TFH cells provide specificity to class-switching events remains unclear. There have been no studies using multicolor staining approaches to examine human TFH cells in situ in secondary lymphoid organs (SLOs) or tertiary lymphoid organs (TLOs). The possibility that chronic disease states exhibiting polarized isotype switching could provide novel insights into specialized TFH cells served as the rationale for undertaking this study. In the studies of Ueno et al (Morita et al, 2011; Ueno et al, 2015) on blood TFH subsets, TFH1 cells secrete IFN-γ upon activation and have limited isotype-switching activity when examined in in vitro coculture experiments. TFH2 cells secrete IL-4 after many days of in vitro stimulation and can mediate class switching to IgA, IgE, and essentially all IgG isotypes, including IgG4. TFH17 cells secrete IL-17 following activation and are promiscuous

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Conclusion