Distinct CD8 T Cell Populations with Differential Exhaustion Profiles Associate with Secondary Complications in Common Variable Immunodeficiency
Adam Klocperk, David Friedmann, Alexandra Emilia Schlaak, Susanne Unger, Zuzana Paračková, Sigune Goldacker, Anna Šedivá, Bertram Bengsch, Klaus Warnatz
Abstract
PURPOSE: Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency, with heterogeneous clinical presentation. Our goal was to analyze CD8 T cell homeostasis in patients with infection only CVID, compared to those additionally affected by dysregulatory and autoimmune phenomena. METHODS: We used flow and mass cytometry evaluation of peripheral blood of 40 patients with CVID and 17 healthy donors. RESULTS: CD8 T cells are skewed in patients with CVID, with loss of naïve and increase of effector memory stages, expansion of cell clusters with high functional exhaustion scores, and a highly activated population of cells with immunoregulatory features, producing IL-10. These findings correlate to clinically widely used B cell-based EURO classification. Features of exhaustion, including loss of CD127 and CD28, and expression of TIGIT and PD-1 in CD8 T cells are strongly associated with interstitial lung disease and autoimmune cytopenias, whereas CD8 T cell activation with elevated HLA-DR and CD38 expression predict non-infectious diarrhea. CONCLUSION: We demonstrate features of advanced differentiation, exhaustion, activation, and immunoregulatory capabilities within CD8 T cells of CVID patients. Assessment of CD8 T cell phenotype may allow risk assessment of CVID patients and provide new insights into CVID pathogenesis, including a better understanding of mechanisms underlying T cell exhaustion and regulation.