Chronically Activated T-cells Retain Their Inflammatory Properties in Common Variable Immunodeficiency

Abstract

Purpose Immune dysregulation complications cause significant morbidity and mortality in common variable immunodeficiency (CVID), but the underlying pathophysiology is poorly understood. While CVID is primarily considered a B-cell defect, resulting in the characteristic hypogammaglobulinemia, T-cells may also contribute to immune dysregulation complications. Here, we aim to further characterize T-cell activation and regulation in CVID with immune dysregulation (CVIDid). Methods Flow cytometry was performed to investigate T-cell differentiation, activation and intracellular cytokine production, negative regulators of immune activation, regulatory T-cells (Treg), and homing markers in 12 healthy controls, 12 CVID patients with infections only (CVIDio), and 20 CVIDid patients. Results Both CD4\u2009+\u2009and CD8\u2009+\u2009T-cells in CVIDid showed an increased activation profile (HLA-DR\u2009+\u2009, Ki67\u2009+\u2009, IFNγ\u2009+) when compared to CVIDio, with concomitant upregulation of negative regulators of immune activation PD1, LAG3, CTLA4, and TIGIT. PD1\u2009+\u2009and LAG3\u2009+\u2009subpopulations contained equal or increased frequencies of cells with the capacity to produce IFNγ, Ki67, and/or GzmB. The expression of PD1 correlated with serum levels of CXCL9, 10, and 11. Treg frequencies were normal to high in CVIDid, but CVIDid Tregs had reduced CTLA-4 expression, especially on CD27\u2009+\u2009effector Tregs. Increased migratory capacity to inflamed and mucosal tissue was also observed in CVIDid T-cells. Conclusion CVIDid was characterized by chronic activation of peripheral T-cells with preserved inflammatory potential rather than functional exhaustion, and increased tissue migratory capacity. While Treg numbers were normal in CVIDid Tregs, low levels of CTLA-4 indicate possible Treg dysfunction. Combined studies of T-cell dysfunction and circulating inflammatory proteins may direct future treatment strategies. Supplementary Information The online version contains supplementary material available at 10.1007/s10875-021-01084-6.