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

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Abstract

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.

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Data Availability

The authors confirm that the de-identified data supporting the findings of this study are available within the article and its supplementary materials.

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Funding

This work was supported in part by grants from the National Institutes of Health (1R01AG056728 and R01AG055362 to IK and K23AI115001 to NR).

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Authors and Affiliations

  1. Section of Rheumatology, Allergy and Immunology, Departments of Internal Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA

    Junghee J. Shin, Min Sun Shin, Srikar Reddy, Paula J. Whittington & Insoo Kang

  2. Section of Pulmonology, Allergy, Immunology and Sleep Medicine, Department of Pediatrics, Yale University School of Medicine, New Haven, CT, 06520, USA

    Jason Catanzaro & Gary Soffer

  3. Division of Allergy and Immunology, Nationwide Children’s Hospital, Columbus, OH, 43212, USA

    Jennifer R. Yonkof, Peter J. Mustillo & Roshini S. Abraham

  4. Laboratory of Clinical Immunology and Microbiology, National Institution of Allergy and Infectious Diseases, NIH, Bethesda, MD, 20893, USA

    Ottavia Delmonte, Keith Sacco & Luigi D. Notarangelo

  5. Department of Allergy and Immunology, Mid-Atlantic Permanente Medical Group of Kaiser Permanente, Rockville, MD, 20852, USA

    Paula J. Whittington

  6. Division of Allergy and Immunology, The Children’s Hospital of Philadelphia, Philadelphia, PA, 19104, USA

    Kathleen E. Sullivan & Neil Romberg

  7. Department of Pediatrics, The Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA

    Kathleen E. Sullivan & Neil Romberg

  8. Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH, 43212, USA

    Roshini S. Abraham

Authors
  1. Junghee J. Shin
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  2. Jason Catanzaro
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  9. Gary Soffer
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  13. Roshini S. Abraham
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  15. Insoo Kang
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Corresponding author

Correspondence to Insoo Kang.

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This study was approved by the Institutional Review Boards of all participating institutions with appropriate consents (see subjects in the “Methods” section).

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Shin, J.J., Catanzaro, J., Yonkof, J.R. et al. Infectious Complications Predict Premature CD8+ T-cell Senescence in CD40 Ligand-Deficient Patients. J Clin Immunol 41, 795–806 (2021). https://doi.org/10.1007/s10875-021-00968-x

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