Synergistic blockade of TIGIT and PD-L1 increases type-1 inflammation and improves parasite control during murine blood-stage Plasmodium yoelii non-lethal infection

ABSTRACT Pro-inflammatory immune responses are rapidly suppressed during blood-stage malaria but the molecular mechanisms driving this regulation are still incompletely understood. In this study, we show that the co-inhibitory receptors TIGIT and PD-1 are upregulated and co-expressed by antigen-specific CD4 + T cells (ovalbumin-specific OT-II cells) during non-lethal Plasmodium yoelii expressing ovalbumin ( Py NL -OVA ) blood-stage infection. Synergistic blockade of TIGIT and PD-L1, but not individual blockade of each receptor, during the early stages of infection significantly improved parasite control during the peak stages (days 10–15) of infection. Mechanistically, this protection was correlated with significantly increased plasma levels of IFN-γ, TNF, and IL-2, and an increase in the frequencies of IFN-γ-producing antigen-specific T-bet + CD4 + T cells (OT-II cells), but not antigen-specific CD8 + T cells (OT-I cells), along with expansion of the splenic red pulp and monocyte-derived macrophage populations. Collectively, our study identifies a novel role for TIGIT in combination with the PD1-PD-L1 axis in regulating specific components of the pro-inflammatory immune response and restricting parasite control during the acute stages of blood-stage Py NL infection.