The elusive identity of CXCR5⁺ CD8 T cells in viral infection and autoimmunity: Cytotoxic, regulatory, or helper cells?

Our knowledge on the development and functions of CXCR5⁺ CD8 T cells is rudimentary when confronted to other extensively studied CD8 T cell subsets. A decade ago, it became apparent that CD8 T cells possess two additional and rather unexpected functional properties other than cytotoxicity, one involving what is known as B cell helper activity and the other involving suppression of self-reactive responses generally known as T cell regulation. Although these adaptive responses are well-known functions of CD4 T cells, they remain poorly understood in CD8 T cells. Thus far, three subsets of CXCR5⁺ CD8 T cells have been identified. The first subset of CXCR5⁺ CD8 T cells is present in chronic viral infections and is referred to as progenitors of exhausted T cells showing heightened proliferative and cytotoxic properties as compared to CXCR5^- CD8 T cells. The second subset of CXCR5⁺ CD8 T cells functions as regulatory T cells that inhibit CD4 T follicular helper (Tfh) humoral responses and the development of autoantibodies. The third subset of CXCR5⁺ CD8 T cells was identified in mice with mutations in immunoregulatory genes (i.e. FOXP3 and IL-2-deficient mice) and involves CD8 T cells with Tfh-like properties that promote humoral autoimmunity through interaction with B cells. This review summarizes the phenotype, function, and differentiation of CXCR5⁺ CD8 T cells.