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Purpose: A subset of common variable immunodeficiency (CVID) patients either presents with or develops autoimmune and lymphoproliferative complications, such as granulomatous lymphocytic interstitial lung disease (GLILD), a major cause of morbidity and mortality in CVID. While a myriad of phenotypic lymphocyte derangements has been associated with and described in GLILD, defects in T and B cell antigen receptor (TCR/BCR) signaling in CVID and CVID with GLILD (CVID/GLILD) remain undefined, hindering discovery of biomarkers for disease monitoring, prognostic prediction, and personalized medicine approaches., Methods: To identify perturbations of immune cell subsets and TCR/BCR signal transduction, we applied mass cytometry analysis to peripheral blood mononuclear cells (PBMCs) from healthy control participants (HC), CVID, and CVID/GLILD patients., Results: Patients with CVID, regardless of GLILD status, had increased frequency of HLADR + CD4 + T cells, CD57 + CD8 + T cells, and CD21 lo B cells when compared to healthy controls. Within these cellular populations in CVID/GLILD patients only, engagement of T or B cell antigen receptors resulted in discordant downstream signaling responses compared to CVID. In CVID/GLILD patients, CD21 lo B cells showed perturbed BCR-mediated phospholipase C gamma and extracellular signal-regulated kinase activation, while HLADR + CD4 + T cells and CD57 + CD8 + T cells displayed disrupted TCR-mediated activation of kinases most proximal to the receptor., Conclusion: Both CVID and CVID/GLILD patients demonstrate an activated T and B cell phenotype compared to HC. However, only CVID/GLILD patients exhibit altered TCR/BCR signaling in the activated lymphocyte subsets. These findings contribute to our understanding of the mechanisms of immune dysregulation in CVID with GLILD., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)