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

Abstract

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