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

Abstract

Distinct TFH subsets that influence specific class-switching events are assumed to exist, but the accumulation of isotype-specific TFH subsets in secondary and tertiary lymphoid organs has not been hitherto demonstrated. IL-4 expressing TFH cells are surprisingly sparse in human secondary lymphoid organs. In sharp contrast, in IgG4-related disease (IgG4-RD), a disorder characterized by polarized Ig class switching, most TFH cells in tertiary and secondary lymphoid organs 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 both from PD1hi TFH cells that do not secrete IL-4 and IL4-secreting non-TFH cells. Unlike IgG4-RD, IL-4+ TFH cells are rarely found in tertiary lymphoid organs in Sjogrens syndrome, a disorder in which IgG4 is not elevated. The proportion of CD4+IL-4+BATF+ T cells as well as of 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 sub-population in human tertiary and secondary lymphoid organs that is linked to IgG4 class switching.