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CXCR5 + CD8 T cells have attracted significant interest within multiple areas of immunology, cancer, and infection. This is in part due to their apparent dual functionality. These cells perform as cytotoxic cells in a variety of infection states including LCMV, HBV, HIV and SIV. However, CXCR5 + CD8 T cells also associate with B cells in peripheral organs and function to stimulate B cell proliferation, antibody/B cell receptor class-switch, and antibody production. CXCR5 + CD8 T cells are similar to CXCR5 + CD4 T follicular helpers in their genetic make-up, B cell interactions, and functionality despite possessing elevated programmed cell death 1 and cytotoxic proteins. Within cancer CXCR5 + CD8 T cells have risen as potential prognostic markers for overall survival and are functionally cytotoxic within tumor microenvironments. In inflammatory disease and autoimmunity, CXCR5 + CD8 T cells are implicated in disease progression. During viral infection and cancer, CXCR5 expression on CD8 T cells generally is indicative of progenitor memory stem-like exhausted cells, which are more responsive to immune checkpoint blockade therapy. The use of immune checkpoint inhibitors to overcome immune exhaustion in cancer, and subsequent consequence of immune adverse events, highlights the dual nature of the cellular immune response. This review will detail the functionality of CXCR5 + CD8 T cells in cancer and autoimmunity with potential repercussions during immune checkpoint blockade therapy discussed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Turner, Mullins and Hoyer.)

IL-2Rα, in part, comprises the high affinity receptor for IL-2, a cytokine important in immune proliferation, activation, and regulation. IL-2Rα deficient mice (IL-2Rα-KO) develop systemic autoimmune disease and die from severe anemia between 18 and 80 days of age. These mice develop kinetically distinct autoimmune progression, with approximately a quarter dying by 21 days of age and half dying after 30 days. This research aims to define immune parameters and cytokine signaling that distinguish cohorts of IL-2Rα-KO mice that develop early- versus late-stage autoimmune disease. To investigate these differences, we evaluated complete blood counts (CBC), antibody binding of RBCs, T cell numbers and activation, hematopoietic progenitor changes, and signaling kinetics, during autoimmune hemolytic anemia (AIHA) and bone marrow failure. We identified several alterations that, when combined, correlate to disease kinetics. Early onset disease correlates with anti-RBC antibodies, lower hematocrit, and reduced IL-7 signaling. CD8 regulatory T cells (Tregs) have enhanced apoptosis in early disease. Further, early and late end stage disease, while largely similar, had several differences suggesting distinct mechanisms drive autoimmune disease kinetics. Therefore, IL-2Rα-KO disease pathology rates, driven by T cell signaling, promote effector T cell activation and expansion and Treg dysfunction.