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.

Center for Chronic Immunodeficiency Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

Clinic for Internal Medicine 2 Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

Department of Immunology 2nd Faculty of Medicine Charles University and University Hospital in Motol Prague Czech Republic

Division of Immunodeficiency Department of Rheumatology and Clinical Immunology Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

Faculty of Biology University of Freiburg Freiburg Germany

German Cancer Consortium partner site Freiburg Freiburg Germany

Institute of Experimental Immunology University of Zurich Zurich Switzerland

Signaling Research Centres BIOSS and CIBSS University of Freiburg Freiburg Germany

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