Clonal composition and persistence of antigen-specific circulating T follicular helper cells.

T follicular helper (T FH ) cells play an essential role in promoting B cell responses and antibody affinity maturation in germinal centres (GC). A subset of memory CD4 + T cells expressing the chemokine receptor CXCR5 has been described in human blood as phenotypically and clonally related to GC T FH cells. However, the antigen specificity and relationship of these circulating T FH (cT FH ) cells with other memory CD4 + T cells remain poorly defined. Combining antigenic stimulation and T cell receptor (TCR) Vβ sequencing, we found T cells specific to tetanus toxoid (TT), influenza vaccine (Flu) or Candida albicans (C.alb) in both cT FH and non-cT FH subsets, although with different frequencies and effector functions. Interestingly, cT FH and non-cT FH cells specific for C.alb or TT had a largely overlapping TCR Vβ repertoire while the repertoire of Flu-specific cT FH and non-cT FH cells was distinct. Furthermore, Flu-specific but not C.alb-specific PD-1 + cT FH cells had a "GC T FH -like" phenotype, with overexpression of IL21, CXCL13, and BCL6. Longitudinal analysis of serial blood donations showed that Flu-specific cT FH and non-cT FH cells persisted as stable repertoires for years. Collectively, our study provides insights on the relationship of cT FH with non-cT FH cells and on the heterogeneity and persistence of antigen-specific human cT FH cells. This article is protected by copyright. All rights reserved.