Alterations in CD8<sup>+</sup> T cell phenotype and function in the peripheral blood of <em>PIK3CD </em>gain-of-function patients — ASN Events
  1. Schedule
  2. Workshop 7: Infection and Immunity 2
  3. Alterations in CD8+ T cell phenotype and function in the peripheral blood of PIK3CD gain-of-function patients

Alterations in CD8+ T cell phenotype and function in the peripheral blood of PIK3CD gain-of-function patients (#74)

Emily SJ Edwards 1 2 , Theresa Cole 3 , Melanie Wong 4 , Kaan Boztug 5 6 , Peter Su 4 , Emma Gostick 7 , David A Price 7 8 , Isabelle Meyts 9 , Gulbu Uzel 10 , Stuart G Tangye 1 2
  1. Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. St Vincent's Clinical School, UNSW, Sydney, USA
  3. Department of Allergy and Immunology, Royal Children's Hospital, Melbourne , VIC, Australia
  4. Department of Allergy and Immunology, Children's Hospital at Westmead, Sydney, NSW, Australia
  5. CemM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
  6. Department of Paediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
  7. Infection and Immunity, Cardiff University, Cardiff, UK
  8. Vaccine Research Center, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, USA
  9. University Hospitals Leuven and KU Leuven, Leuven, Belgium
  10. Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, NIH, Bethesda, USA

CD8+ T cells play a pivotal role in controlling infections by viruses, such as Epstein Barr Virus (EBV). Due to the efficacy of these responses healthy individuals are largely asymptomatic upon primary infection. In contrast, immunodeficient patients including those with heterozygous, germline gain-of-function mutations in PIK3CD (encoding the p110d catalytic subunit of PI3K) are characterized by susceptibility to EBV-induced disease. Previous publications have demonstrated the constitutive hyperactivation of the PI3K-Akt-mTOR pathway in CD8+ T cells. In order to understand how PIK3CD GOF mutations contribute to EBV susceptibility, we have utilized polychromatic flow cytometry to enumerate the phenotypic and functional attributes of total and EBV-specific CD8+ T cells. Our results demonstrate an altered CD8+ T cell phenotype with a skewed TEM/TEMRA phenotype in patients with PIK3CD mutations. Although similar frequencies of EBV-specific CD8+ T cells were detected in patients and healthy donors, total and EBV-specific CD8+ T cells are hyperactivated as evidenced by significant upregulation of regulatory molecules CD95, CD160 and 2B4 as well as the cytotoxic mediator Granzyme B. In addition, CD57 and PD-1 are overexpressed indicating immunosenescence of CD8+ T cells. Functional analyses show that cytokine and cytolytic marker expression is dysregulated in these patients upon TCR stimulation. In addition, we have shown that CD8+ T cells from these patients are highly susceptible to restimulation-induced cell death.

In conclusion, PIK3CD GOF mutations perturb expression of key regulatory and cytotoxic markers on CD8+ T cells, which is associated with aberrant cytokine expression and suspected cytotoxic dysfunction towards EBV-infected targets. Collectively, these perturbations underlie the increased susceptibility to EBV and EBV-induced disease in these individuals. Further investigation will provide new insights into the generation and function of CD8+ T cells in the control of EBV, which will be important in the treatment of EBV-associated diseases, and EBV vaccine development.

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