The CXCR3 chemokine receptor is critical for the protective immune response to Plasmodiumparasite infection of the liver.

Abstract No highly efficacious anti-malaria vaccine exists, but whole parasite immunization (WPI)where hosts receive live attenuated Plasmodium parasites that arrest in the liver is the only strategy that confers complete protection against future Plasmodium parasite infection. Liver-resident memory CD8 T cells (TRM)that express the chemokine receptor, CXCR3, are essential for WPI-induced protection. Yet, whether CXCR3-dependent signaling plays a functional role in anti-parasite T RMimmunity is not fully understood. RNA-seq analyses on hepatocytes isolated from Plasmodium-infected mice showed an upregulation of the CXCR3-dependent chemokines, CXCL9 and CXCL10. We examined protection in WT and CXCR3 −/−mice upon WPI and report that in contrast to WT animals, CXCR3 −/−mice exhibit impaired control of a parasite challenge given 40 days after immunization. Next, we set out to enumerate T cell recruitment and T RMnumbers in the liver after WPI. CXCR3 −/−mice exhibited reduced CD8 T cell numbers early after immunization yet by day 40 contained equivalent T RMnumbers as compared to immunized WT counterparts. We hypothesize that while CXCR3 signaling is critical for early recruitment of activated CD8 T cells into the Plasmodium-infected liver, other chemokines compensate for the loss of CXCR3 ensuring that equivalent numbers of CD8 T cells are eventually recruited into the liver. However, as CXCR3 −/−mice exhibit impaired control of infection despite containing equivalent T RMnumbers, the CXCR3 axis must play other unidentified roles. Immune cells are known to be asymmetrically positioned in the liver. Ongoing studies will determine if CXCR3 is critical for the optimal positioning and function of liver T RMs after parasite infection.