Inverse relationship between CD40L expression and cytolytic molecule expression by CD8+CXCR5+ T follicular cytotoxic cells in colorectal cancer

Abstract CXCR5+ CD8 T cells, sometimes termed T follicular cytotoxic (Tfc) cells, are characterized by high proinflammatory cytokine and cytolytic molecule expression and low exhaustion and checkpoint molecule expression. Additionally, Tfc cells could promote B cell responses and support Ig release. It is yet unclear how Tfc cells could help B cells when they have the potential to mediate cytotoxicity at the same time. In this study, we found that Tfc cells expressed significantly higher levels of CD40L than non-Tfc CD8 T cells. Interestingly, Tfc cells from colorectal cancer (CRC) patients presented significantly higher CD40L than Tfc cells from healthy controls in a manner that was associated with CRC stage. Coincubation of Tfc cells and autologous B cells resulted in higher CD40L expression in a time-dependent manner. Interestingly, activated Tfc cells, when incubated with B cells, presented rapid downregulation of perforin and granzyme B. In general, greater than 50% of tumor-infiltrating Tfc cells expressed CD40L. In addition, the level of CD40L in tumor-infiltrating Tfc cells was higher in stage IV CRC patients than in stage II and stage III CRC patients. Interestingly, the levels of perforin and granzyme B expression by tumor-infiltrating Tfc cells were inversely correlated with the level of CD40L expression by tumor-infiltrating Tfc cells. Overall, we demonstrated that an inverse association existed between CD40L and cytotoxic molecule expression in Tfc cells from CRC patients.