The TH1 phenotype of follicular helper T cells indicates an IFN-γ-associated immune dysregulation in patients with CD21low common variable immunodeficiency

Background: A subgroup of patients with common variable immunodeficiency (CVID) experience immune dysregulation manifesting as autoimmunity, lymphoproliferation, and organ inflammation and thereby increasing morbidity and mortality. Therefore treatment of these complications demands a deeper comprehension of their cause and pathophysiology. Objectives: On the basis of the identification of an interferon signature in patients with CVID with secondary complications and a skewed follicular helper T-cell differentiation in defined monogenic immunodeficiencies, we sought to determine the profile of CD4 memory T cells in blood and secondary lymphatic tissues of these patients. Methods: We quantified T(H)1/T(H)2/T(H)17 CD4 memory T cells in blood and lymph nodes of patients with CVID using flow cytometry, analyzed their function, and correlated all findings to the burden of immune dysregulation. Results: Patients with CVID with immune dysregulation had a skewed memory CD4 T-cell differentiation toward a CXCR3(+)CCR6(-) T(H)1 phenotype both in blood and lymph nodes. Consistent with our phenotypic findings, we observed a higher IFN-gamma production in peripheral CD4 memory T cells and lymph node-derived follicular helper T cells of patients with CVID compared with those of healthy control subjects. Increased IFN-gamma production was accompanied by a poor germinal center output, an accumulation of T-box transcription factor (T-bet)(+) B cells in lymph nodes, and an accumulation of T-bet(+)CD21(low) B cells in peripheral blood of affected patients. Conclusion: Identification of excessive IFN-gamma production by blood and lymph node-derived T cells of patients with CVID with immune dysregulation will offer new therapeutic avenues for this subgroup. CD21(low) B cells might serve as a marker of this IFN-gamma-associated dysregulation.