Poster Presentation Lorne Infection and Immunity 2022

Cytomegalovirus infection drives an atypical human Vδ2+ T cell compartment (#106)

Daniel Arsovski 1 , Anouk von Borstel 1 , Priyanka Chevour 1 , Jelte M.M. Krol 2 3 , Andrea A. Berry 4 , Effie Y.H. Nomicos 5 , Justin A. Boddey 2 3 , Kirsten E. Lyke 4 , Kim C. Williamson 6 , Barry Slobedman 7 , Nicole A. Mifsud 1 , Jamie Rossjohn 1 , Martin S. Davey 1
  1. Monash University, Clayton, Victoria, Australia
  2. The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  3. University of Melbourne, Melbourne, VIC
  4. Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA
  5. Parasitology and International Programs Branch, Division of Microbiology and infectious Diseases, NIAID, NIH, Bethesda, MD, USA
  6. Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
  7. University of Sydney, Sydney, NSW, Australia

Human Vδ2+ T cells form the predominant human γδ T cell population in peripheral blood and possess a semi-invariant Vγ9 and Vδ2 T cell receptor (TCR) chain pairing. This TCR repertoire allows Vδ2+ T cells to function in an innate-like manner towards pyrophosphate metabolites (PAg) and mount TCR-dependent immune responses to bacterial and parasitic pathogens. Here, we explored the heterogeneity of this Vδ2+ T cell immune response in human Plasmodium falciparum and cytomegalovirus (HCMV) infection. We find that subpopulations of Vδ2+ T cells express alternate and often expanded TCR clonotypes and often these expanded TCRs define a population of PAg unresponsive Granzyme (Gzm) K- CD16+ Vd2+ T cells (atypical Vd2+ T cells). Transcriptional profiling of Vγ9/Vδ2+ T cells indicated that clonally expanded atypical Vδ2+ T cells possess a natural killer cell-like transcriptome compared to PAg reactive GzmK+ Vγ9/Vδ2+ T cells. Using a controlled human malaria infection (CHMI) we found that an individual with a predominant clonally expanded atypical Vδ2+ T cell population fails to mount a response to in vivo P. falciparum infection in humans. Vδ2+ T cells are classically responsive to both PAg and inflammatory cytokines, we found that neither stimuli could induce the clonal selection of the Vδ2+ TCR. Moreover, four repeated CHMIs over two years in individuals with a predominant PAg reactive GzmK+ Vδ2+ T cell population failed to drive clonal selection. However, cytomegalovirus infection in individuals undergoing lung transplant or hematopoietic stem cell transplantation drove the emergence and selection of atypical Vδ2+ T cells. Together, we reveal an alternative compartment of human Vδ2+ T cells that are selected after acute viral infection and that may be an important avenue for harnessing these cells for anti-microbial immunotherapies.