A Portrait of CXCR5⁺ Follicular Cytotoxic CD8⁺ T cells

CD8⁺ T cells differentiate into multiple effector and memory subsets to carry out immune clearance of infected and cancerous cells and provide long-term protection. Recent research identified a CXCR5⁺Tcf1⁺Tim-3⁻ subset that localizes in, or proximal to, B cell follicles in secondary lymphoid organs of mice, non-human primates, and humans, hereby termed follicular cytotoxic T (T_FC) cells. With remarkable similarity to follicular helper T (T_FH) cells, T_FC differentiation is dependent on transcription factors E2A, Bcl6, and Tcf1, but inhibited by other regulators, including Blimp1, Id2, and Id3. This review summarizes the phenotype, function, and differentiation of this new subset. Owing to its follicular location and self-renewal capability, we propose immunotherapeutic strategies to target T_FC cells to potentially treat certain cancers and chronic infections such as HIV-1.