Primary germinal center-resident T follicular helper cells are a physiologically distinct subset of CXCR5hiPD-1hi T follicular helper cells

Abstract

T follicular helper (Tfh) cells are defined by a Bcl6⁺CXCR5^hiPD-1^hi phenotype, but only a minor fraction of these reside in germinal centers (GCs). Here, we examined whether GC-resident and -nonresident Tfh cells share a common physiology and function. Fluorescently labeled, GC-resident Tfh cells in different mouse models were distinguished by low expression of CD90. CD90^neg/lo GCTfh cells required antigen-specific, MHCII⁺ B cells to develop and stopped proliferating soon after differentiation. In contrast, nonresident, CD90^hi Tfh (GCTfh-like) cells developed normally in the absence of MHCII⁺ B cells and proliferated continuously during primary responses. The TCR repertoires of both Tfh subsets overlapped initially but later diverged in association with dendritic cell-dependent proliferation of CD90^hi GCTfh-like cells, suggestive of TCR-dependency seen also in TCR-transgenic adoptive transfer experiments. Furthermore, the transcriptomes of CD90^neg/lo and CD90^hi GCTfh-like cells were enriched in different functional pathways. Thus, GC-resident and nonresident Tfh cells have distinct developmental requirements and activities, implying distinct functions.

Keywords: S1pr2; T:B interaction; Tfh cells; affinity maturation; germinal centers; humoral immunity.