CD8 T cells are infrequently considered part of germinal center reactions. Yet, a distinct CXCR5+ CD8 T cell subset identified within the B cell follicle and germinal center in situations of chronic antigen has recently been defined. CXCR5+ CD8 T cells maintain transcriptional and phenotypic features consistent with the CD8 T cell nomenclature of a non-exhausted, effector memory population. CD8 T cell localization to the B cell follicle suggests a functional profile similar to CD4 T follicular helper cells that are licensed to promote B cell responses. The functional mechanisms defined under different immune settings, while largely similar, differentially control disease pathogenesis. CXCR5+ CD8 T cells control viral load during infection, and also promote antibody-mediated autoimmune disease progression. The existence of this novel CXCR5+ CD8 T cell subset in human and murine models of disease may provide a paradigm shift in our understanding of germinal center reactions.

CD8 T cells can play both a protective and pathogenic role in inflammation and autoimmune development. Recent studies have highlighted the ability of CD8 T cells to function as T follicular helper (Tfh) cells in the germinal center in the context of infection. However, whether this phenomenon occurs in autoimmunity and contributes to autoimmune pathogenesis is largely unexplored. In this study, we show that CD8 T cells acquire a CD4 Tfh profile in the absence of functional regulatory T cells in both the IL-2–deficient and scurfy mouse models. Depletion of CD8 T cells mitigates autoimmune pathogenesis in IL-2–deficient mice. CD8 T cells express the B cell follicle–localizing chemokine receptor CXCR5, a principal Tfh transcription factor Bcl6, and the Tfh effector cytokine IL-21. CD8 T cells localize to the B cell follicle, express B cell costimulatory proteins, and promote B cell differentiation and Ab isotype class switching. These data reveal a novel contribution of autoreactive CD8 T cells to autoimmune disease, in part, through CD4 follicular-like differentiation and functionality.

Coccidioidomycosis is a fungal, respiratory disease caused by Coccidioides immitis and Coccidioides posadasii. This emerging infectious disease ranges from asymptomatic to pulmonary disease and disseminated infection. Most infections are cleared with little to no medical intervention whereas chronic disease often requires life-long medication with severe impairment in quality of life. It is unclear what differentiates hosts immunity resulting in disease resolution versus chronic infection. Current understanding in mycology-immunology suggests that chronic infection could be due to maladaptive immune responses. Immunosuppressed patients develop more severe disease and mouse studies show adaptive Th1 and Th17 responses are required for clearance. This is supported by heightened immunosuppressive regulatory responses and lowered anti-fungal T helper responses in chronic Coccidioides patients. Diagnosis and prognosis is difficult as symptoms are broad and overlapping with community acquired pneumonia, often resulting in misdiagnosis and delayed treatment. Furthermore, we lack clear biomarkers of disease severity which could aid prognosis for more effective healthcare. As the endemic region grows and population increases in endemic areas, the need to understand Coccidioides infection is becoming urgent. There is a growing effort to identify fungal virulence factors and host immune components that influence fungal immunity and relate these to patient disease outcome and treatment. This review compiles the known immune responses to Coccidioides spp. infection and various related fungal pathogens to provide speculation on Coccidioides immunity.