PD-1 and ICOS are coexpressed in T follicular helper cells but define three stages of maturation of T follicular regulatory cells

Humoral responses to infection or vaccination require T cell-B cell interactions. T follicular helper (TFH) cells drive germinal center (GC) responses by providing help to B cells, whereas T follicular regulatory (TFR) cells regulate them. Both mature GC-located TFH and TFR cells are widely characterized by the expression of ICOS and PD-1. However, although human TFR cells share many phenotypic characteristics with TFH cells, we found that ICOS and PD-1 are up-regulated differently in each. Although TFH cells express these proteins synchronously during maturation, they define three maturation stages in TFR cells. TFR cells in an intermediate maturation stage express ICOS, and it is only at the last stage of differentiation that both molecules are expressed at high levels. Although most TFR cells within the B cell follicle are PD-1-, the TFR within the GC are ICOS+PD-1+. These results show that TFH and TFR cells within human lymphoid tissue follow distinct maturation stages.

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