Infectious Complications Predict Premature CD8+ T-cell Senescence in CD40 Ligand-Deficient Patients

J Clin Immunol. 2021 May;41(4):795-806. doi: 10.1007/s10875-021-00968-x. Epub 2021 Jan 26.


Purpose: CD40 ligand (CD40L)-deficient patients display increased susceptibilities to infections that can be mitigated with effective prophylactic strategies including immunoglobulin G (IgG) replacement and prophylactic antibiotics. CD8+ T-cell senescence has been described in CD40L deficiency, but it is unclear if this is an intrinsic feature of the disease or secondary to infectious exposures. To address this question, we assessed CD8+ T-cell senescence and its relationship to clinical histories, including prophylaxis adherence and infections, in CD40L-deficient patients.

Methods: Peripheral CD8+ T-cells from seven CD40L-deficient patients and healthy controls (HCs) were assessed for senescent features using T-cell receptor excision circle (TREC) analysis, flow cytometry, cytometry by time of flight (CyTOF) and in vitro functional determinations including CMV-specific proliferation and cytokine release assays.

Results: Three patients (5, 28, and 34 years old) who were poorly adherent to immunoglobulin G replacement and Pneumocystis jirovecii pneumonia (PJP) prophylaxis and/or experienced multiple childhood pneumonias (patient group 1) had an expansion of effector memory CD8+ T-cells with the senescent phenotype when compared to HCs. Such changes were not observed in the patient group 2 (four patients, 16, 22, 24, and 33 years old) who were life-long adherents to prophylaxis and experienced few infectious complications. CyTOF analysis of CD8+ T-cells from the 5-year-old patient and older adult HCs showed similar expression patterns of senescence-associated molecules.

Conclusions: Our findings support that recurrent infections and non-adherence to prophylaxis promote early CD8+ T-cell senescence in CD40L deficiency. Premature senescence may increase malignant susceptibilities and further exacerbate infectious risk in CD40L-deficient patients.

Keywords: CD8+ T-cell senescence; Pneumocystis jirovecii pneumonia (PJP) prophylactic antibiotics; X-linked CD40 ligand deficiency; class switching recombination defect; combined immunodeficiency; immunoglobulin replacement therapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Biomarkers
  • CD40 Ligand / deficiency*
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism*
  • Case-Control Studies
  • Cellular Senescence / genetics*
  • Child, Preschool
  • Genes, X-Linked
  • Genetic Association Studies / methods
  • Genetic Predisposition to Disease
  • Humans
  • Immune System Diseases / complications*
  • Immune System Diseases / etiology*
  • Immunophenotyping
  • Infections / diagnosis*
  • Infections / etiology*
  • Pedigree
  • Phenotype
  • Prognosis
  • Receptors, Antigen, T-Cell
  • Young Adult


  • Biomarkers
  • Receptors, Antigen, T-Cell
  • CD40 Ligand