Poster Presentation Australasian Society for Immunology Annual Scientific Meeting 2014

Effect of mutations in PI3 kinase p110d on the phenotype and function of EBV-specific human CD8+ T-cells  (#299)

Emily SJ Edwards 1 , Pamela Schwartzberg 2 , Gulbu Uzel 3 , Stuart G Tangye 1
  1. Garvan Institute of Medical Research, Sydney, NSW, Australia
  2. National Human Genome Research Institute, NIH, Bethesda, Maryland, USA
  3. Immunopathogenesis Section, Laboratory of Clinical Infectious Diseases, NIH, Bethesda, USA

Induction of a robust T-cell response is paramount in the efficient control of infection and malignancy. CD8+ T-cell activation via recognition of virally-infected or malignantly-transformed cells results in clonal expansion, differentiation and acquisition of effector function. In particular, CD8+ T-cells mediate the lysis and elimination of target cells via the release of cytolytic substances such as perforin and granzymes, as well as cytokines. In healthy individuals, T-cell responses are eloquently controlled by an intricate balance between stimulatory (antigen receptors, co-stimulatory molecules, adhesion molecules and cytokine/chemokine receptors), and inhibitory (inhibitory receptors and ligands) signals. The importance of this exquisite control mechanism is demonstrated in the development of diseases associated with mutations in key signaling pathways controlling immunity, including immunodeficiencies. Patients have been identified with heterozygous, germline gain of function mutations in PIK3CD (which encodes the p110d catalytic component of PI3 kinase). PIK3CD is predominantly expressed in leukocytes and is critical for lymphocyte function.

In healthy individuals, primary EBV infection is often asymptomatic with CD8+ T-cells being largely responsible for viral control. However, patients with PIK3CD mutations present with uncontrolled EBV and/or CMV viremia.

Previous studies have reported an alteration of CD8+ T-cell phenotype in these patients, with a skewing towards a predominant TEMRA phenotype, and a significant reduction in naïve CD8 T-cell frequencies. We have extended these findings to enumerate the functional and phenotypic attributes of EBV CD8+ T-cells in PIK3CD mutant patients. We identified inflation of EBV-specific CD8+ T-cell frequencies in a subset of patients. Which is concomitant with upregulation of inhibitory molecules including PD-1, CD57 and 2B4. This 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-susceptible individuals, as well as in the development of vaccines against EBV.