Follicular B helper T cell activity is confined to CXCR5hiICOShi CD4 T cells and is independent of CD57 expression

The generation of high-affinity antibody-secreting plasma cells critically depends on the presence of CD4 T cells during the germinal center (GC) reaction. GC T cells are so far incompletely characterized in terms of phenotype and function. Here, we show that human follicular B helper T (T-FH) cells are characterized by high expression of the homeostatic chemokine receptor CXCR5 and the costimulatory molecule ICOS, but not CD57 expression. CXCR5(hi)ICOS(hi)CD4 T cells are the most potent inducers of IgG production that also secrete large amounts of the B cell-attracting chemokine CXCL13. CXCR5(hi)ICOS(hi) CD4 T cells differ from other tonsillar CD4 T cell subsets in their stimulatory activity, proliferative capacity and susceptibility to apoptosis. Large-scale gene expression analysis revealed that TFH cells are only distantly related to CXCR5(-) and CXCR5(+) central memory T (T-CM) as well as effector memory T (T-EM) cells present in the periphery. CXCR5(hi)ICOS(hi)CD4 T cells appear to be terminally differentiated T helper cells that express a unique set of transcription factors related to the Notch signaling pathway and thus differentiate independent of other T helper cell populations.