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

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.

Advances in the diagnosis and management of IgG4 related disease

“…PD1 positive Tfh2 cells drive IgG4 class switch in vitro, enhance proliferation of IgG4 committed B cells, and facilitate differentiation of naive B cells into plasmablasts/plasma cells, resulting in increased IgG4 secretion 464748. Activated Tfh cells expressing interleukin 4 and interleukin 21 are also found in tertiary lymphoid structures of IgG4-RD affected tissues and likely contribute to germinal center formation 1495051. On the other hand, the contribution of T regulatory cells and Th2 cells to disease pathogenesis is controversial.…”

B lymphocytes directly contribute to tissue fibrosis in patients with IgG4-related disease

“…CD19 and IgG 4 double-positive cells infiltrating tissue from patients with IgG 4 -RD also expressed the activation-induced cytidine deaminase, a master regulator of immunoglobulin gene recombination, further supporting ongoing processes of class-switch and somatic hypermutation. 32 To assess the relevance of LOXL2 to the pathogenesis of IgG 4 -RD, we performed multicolor immunofluorescence and quantitative analyses on salivary glands from patients with SS. SS was used as a control condition because of the chronic lymphoplasmacytic inflammation in the absence of significant tissue fibrosis when compared with IgG 4 -RD.…”

Mechanism of Follicular Helper T Cell Differentiation Regulated by Transcription Factors

“…Compared with the healthy controls, c-Maf mRNA expression level and percentage of Tfh cells in peripheral blood mononuclear cells (PBMCs) are increased in patients with chronic immune thrombocytopenia (cITP), and they are decreased after the effective treatment [12]. Compared with the healthy controls, Batf in the submandibular glands and affected lymph nodes is markedly increased in patients with IgG4-RD [17].…”