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

Distinct T follicular helper (T-FH) subsets that influence specific class-switching events are assumed to exist, but the accumulation of isotype-specific T-FH subsets in secondary lymphoid organs (SLOs) and tertiary lymphoid organs has not been hitherto demonstrated. IL-4-expressing T-FH cells are surprisingly sparse in human SLOs. In contrast, in IgG4-related disease (IgG4-RD), a disorder characterized by polarized Ig class switching, most T-FH cells in tertiary and SLOs make IL-4. Human IL-4(+) T-FH cells do not express GATA-3 but express nuclear BATF, and the transcriptomes of IL-4-secreting T-FH cells differ from both PD1hi T-FH cells that do not secrete IL-4 and IL-4-secreting non-T-FH cells. Unlike IgG4-RD, IL-4(+) T-FH cells are rarely found in tertiary lymphoid organs in Sjogren'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 T-FH subpopulation in human tertiary lymphoid organs and SLOs that is linked to IgG4 class switching.