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^hiICOS^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^hiICOS^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 T_FH 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^hiICOS^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.

See accompanying commentary: http://dx.doi.org/10.1002/eji.200636334