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

Roos Marijn Berbers, M. Marlot van der Wal, Joris M. van Montfrans, Pauline M. Ellerbroek, Virgil A.S.H. Dalm, P. Martin van Hagen, Helen L. Leavis*, Femke van Wijk

*Corresponding author for this work

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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 + and CD8 + T-cells in CVIDid showed an increased activation profile (HLA-DR + , Ki67 + , IFNγ +) when compared to CVIDio, with concomitant upregulation of negative regulators of immune activation PD1, LAG3, CTLA4, and TIGIT. PD1 + and LAG3 + subpopulations 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 + effector 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.

Original languageEnglish
Pages (from-to)1621-1632
Number of pages12
JournalJournal of Clinical Immunology
Issue number7
Early online date11 Jul 2021
Publication statusPublished - Oct 2021

Bibliographical note

Funding Information:
This study was financially supported by the Wilhelmina Children’s Hospital Fund (Utrecht, the Netherlands).

Funding Information:
PH reports research grants and personal fees from Shire/Takeda and CSL Behring. VD reports research grants and personal fees from Shire/Takeda, Griffols, Actelion, Novartis, Pharming, and CSL Behring. JM reports personal fees from Shire/Takeda. HL reports research grants from Shire/Takeda. All other authors declare no competing interests.

Publisher Copyright:
© 2021, The Author(s).


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