Heterogeneity of Phenotype and Function Reflects the Multistage Development of T Follicular Helper Cells

Abstract

T follicular helper cells (Tfh) provide crucial signals for germinal center (GC) formation, but Tfh populations are heterogeneous. While PD1hi Tfh are important in the GC response, the function of the PD1lo Tfh-like subset is unknown. We show that these cells, like the PD1hi GC–Tfh, depend upon B cells; however, their entry to follicles is independent of CXCR5 or cognate interactions with B cells. The differentiation into PD1hi Tfh is dependent on MHC class II interactions with B cells and requires CXCR5. Our data suggest a Tfh differentiation pathway that is initially B cell-independent, then dependent on non-cognate B cell interactions, and finally following cognate interaction with B cells and CXCR5-ligands allows the formation of GC–Tfh. The PD1lo Tfh-like cells make early cytokine responses and may represent precursors of CD4 memory cells.

Generation of T follicular helper cells in vitro: requirement for B‐cell receptor cross‐linking and cognate B‐ and T‐cell interaction

“…Some BCL‐6 low/– CXCR5 + CD4 + cells that we also observed in our cultures (Figs and ) might correspond to the earlier stage of Tfh development in vivo (cognate B‐cell‐independent precursors of PD1 hi Tfh cells) . However, in contrast to the situation in vivo we detected these cells also in the absence of DCs.…”

“…Some BCL‐6 low/– CXCR5 + CD4 + cells that we also observed in our cultures (Figs and ) might correspond to the earlier stage of Tfh development in vivo (cognate B‐cell‐independent precursors of PD1 hi Tfh cells) . However, in contrast to the situation in vivo we detected these cells also in the absence of DCs. Since in vivo naive CD4 + T and B cells have distinct histological locations within the secondary lymphoid organs, antigen‐activated B cells have no access to the T‐cell zones to provide naive cognate CD4 T cells with appropriate signals .…”

“…) and OT2 (Figs and ) PD1 hi BCL‐6 + CXCR5 + CD4 + Tfh cells have similarities with in vivo CXCR5 + PD1 hi Tfh cells described by Trüb et al . : generation of both cell types requires cognate interactions with B cells . Interleukin‐4 production by in vitro generated PD1 hi BCL‐6 + CXCR5 + CD4 + Tfh cells also has similarities with mature germinal centre Tfh cells generated after lymphocytic choriomeningitis virus infection in mice .…”

“…Although signals from cognate activated B cells have been shown to play an important role in Tfh cell formation, the absolute requirement for B cells is questioned . Recent data from Trüb et al . demonstrate, however, that the Tfh differentiation pathway is initially B‐cell‐independent, then dependent on non‐cognate B‐cell interactions, and finally following cognate interaction with B cells and CXCR5‐ligands allows the formation of PD1 hi germinal centre Tfh cells.…”

“…Using a variety of bone marrow chimeric mice, Trüb et al . defined multiple steps in the Tfh differentiation pathway that have distinct molecular requirements and may differ in phenotype and function depending on environmental cues.…”