Poster Presentation MIN Spring Retreat 2023

Interleukin-2, not chemokine receptors CXCR3, CXCR5 or CXCR6, controls Th1/Tfh fate bifurcation during blood-stage malaria. (#119)

Takahiro Asatsuma 1 , Marcela L. Moreira 1 , Cameron G. Williams 1 , Hyun Jae Lee 1 , Oliver P. Skinner 1 , Saba Asad 1 , Shihan Li 1 , Thomas N. Burn 1 , Lynette Beattie 1 , Ashraful Haque 1
  1. Microbiology and Immunology, University of Melbourne, located at the Peter Doherty Institute for Infection and Immunity, Melbourne

CD4+ T cell immunity to blood-stage malaria is suboptimal in humans and experimental mice. Two subsets, T-helper 1 (Th1) and follicular helper T cells (Tfh), partially control Plasmodium parasites via IFNγ or by supporting high-affinity antibody production [1]. Discovery of mechanisms controlling Th1/Tfh fate may offer new opportunities for accelerating the onset of immunity to malaria. Previously, we observed early co-expression of chemokine receptors CXCR3 and CXCR5 by Plasmodium­-specific TCR transgenic PbTII cells in P.chabaudi­-­infected mice, prior to their bifurcation towards either Th1 or Tfh fates [2]. We hypothesized here that competition between CXCR3 and CXCR5 influences Th1/Tfh fate in malaria. To test this, genes encoding CXCR3, CXCR5, or CXCR6 were disrupted in naïve PbTIIs via CRISPR/Cas9 and examined for effects on differentiation in vivo. Strikingly, none of these chemokine receptors, either alone or in combination, substantially influenced either PbTII expansion or Th1-differentiation. Instead, by disrupting IL2ra, we determined that early IL-2 signaling, most likely within the first two days of infection, played a critical role in supporting Th1 differentiation, but not clonal expansion. Further experiments suggested IL-2-signalling also controls CD4+ T cell differentiation during experimental vaccination. Hence, the balance between humoral and cellular immunity during malaria infection or vaccination can be modulated by Interleukin-2.

  1. 1. Kurup, S.P., N.S. Butler, and J.T. Harty, T cell-mediated immunity to malaria. Nat Rev Immunol, 2019. 19(7): p. 457-471. 2. Lönnberg, T., et al., Single-cell RNA-seq and computational analysis using temporal mixture modeling resolves TH1/TFHfate bifurcation in malaria. Science Immunology, 2017. 2(9): p. eaal2192.