Follicular CD8 T cells (fCD8, follicular cytotoxic, defined as CD8+CXCR5+) are a specialized population that has recently been shown to be expanded in chronic viral infections and some forms of cancer.
Comparison of fCD8 isolated from secondary lymphoid organs (SLO) of 6 healthy donors and 3 patients with common variable immunodeficiency (CVID).
We found that fCD8 have higher expression of exhaustion markers PD-1, TIGIT, 2B4 and Eomesodermin, high CD57, Granzyme B and lower expression of CD127 and TCF1 compared to conventional CXCR5- CD8s, suggesting terminal differentiation. In CVID, fCD8 were expanded, less differentiated and proliferated more compared to fCD8 of healthy individuals. Healthy donor, but not CVID fCD8 were able to support IgG production by B cells in vitro, however were less potent than follicular helper CD4s.
RNAseq of CVID fCD8s revealed upregulation of several genes compared to healthy donor fCD8s, including B3GAT1 (inducing CD57 expression), HAVCR2 (Tim3), IL10, CTLA4 and FAIM2. Indeed, CVID fCD8 had higher production of IL-10 in vitro and lower sensitivity to Fas-induced apoptosis.
Furthermore, using multidimensional reduction methods we identified two separate fCD8 populations, CD4like and CD8like. CD4like fCD8s shared phenotypic characteristics with TFH CD4 T cells, expressed CD4, low to medium levels of CD8, high CXCR5 and PD1, and were significantly expanded in CVID patients.
We show for the first time the expansion of follicular CD8 T cells in CVID patients with lymphadenopathy, the exhausted/differentiated phenotype of fCD8s in healthy and CVID SLOs and that two separate fCD8 populations co-exist in human germinal centers.