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. 2020 Sep;42(9):e12723.
doi: 10.1111/pim.12723. Epub 2020 May 25.

Combinatorial Tim-3 and PD-1 activity sustains antigen-specific Th1 cell numbers during blood-stage malaria

Rebecca S Dookie  1 , Ana Villegas-Mendez  1 , Hans Kroeze  2 , Jordan R Barrett  3 , Simon J Draper  3 , Blandine M Franke-Fayard  2 , Chris J Janse  2 , Andrew S MacDonald  1 , Kevin N Couper  1
Affiliations

Combinatorial Tim-3 and PD-1 activity sustains antigen-specific Th1 cell numbers during blood-stage malaria

Rebecca S Dookie et al. Parasite Immunol. 2020 Sep.

Abstract

Aims: Co-inhibitory receptors play a major role in controlling the Th1 response during blood-stage malaria. Whilst PD-1 is viewed as the dominant co-inhibitory receptor restricting T cell responses, the roles of other such receptors in coordinating Th1 cell activity during malaria are poorly understood.

Methods and results: Here, we show that the co-inhibitory receptor Tim-3 is expressed on splenic antigen-specific T-bet+ (Th1) OT-II cells transiently during the early stage of infection with transgenic Plasmodium yoelii NL parasites expressing ovalbumin (P yoelii NL-OVA). We reveal that co-blockade of Tim-3 and PD-L1 during the acute phase of P yoelii NL infection did not improve the Th1 cell response but instead led to a specific reduction in the numbers of splenic Th1 OT-II cells. Combined blockade of Tim-3 and PD-L1 did elevate anti-parasite IgG antibody responses. Nevertheless, co-blockade of Tim-3 and PD-L1 did not affect IFN-γ production by OT-II cells and did not influence parasite control during P yoelii NL-OVA infection.

Conclusion: Thus, our results show that Tim-3 plays an unexpected combinatorial role with PD-1 in promoting and/ or sustaining a Th1 cell response during the early phase of blood-stage P. yoelii NL infection but combined blockade does not dramatically influence anti-parasite immunity.

Keywords: CD4+ T cells; T cell exhaustion; co-inhibitory receptors; immunoregulation; malaria.

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References

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