Distinct CD8 T Cell Populations with Differential Exhaustion Profiles Associate with Secondary Complications in Common Variable Immunodeficiency

J Clin Immunol. 2022 Aug;42(6):1254-1269. doi: 10.1007/s10875-022-01291-9. Epub 2022 May 19.


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.

Keywords: Activation; CVID; Differentiation; Exhaustion; Immunodeficiency; T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD28 Antigens
  • CD8-Positive T-Lymphocytes
  • Common Variable Immunodeficiency*
  • HLA-DR Antigens
  • Humans
  • Interleukin-10
  • Programmed Cell Death 1 Receptor / genetics


  • CD28 Antigens
  • HLA-DR Antigens
  • Programmed Cell Death 1 Receptor
  • Interleukin-10