PD-L1, TIM-3, and CTLA-4 Blockade Fails To Promote Resistance to Secondary Infection with Virulent Strains of Toxoplasma gondii

Abstract

T cell exhaustion is a state of hyporesponsiveness that develops during many chronic infections and cancer. Neutralization of inhibitory receptors, or 'checkpoint blockade', can reverse T cell exhaustion and lead to beneficial prognoses in experimental and clinical settings. Whether checkpoint blockade can resolve lethal acute infections is less understood, but may be beneficial in vaccination protocols that fail to elicit sterilizing immunity. Since a fully protective vaccine for any human parasite has yet to be developed, we explored the efficacy of checkpoint inhibitors in a mouse model of re-infection. Mice chronically infected with an avirulent type III strain survive reinfection with the type I RH but not MAS, GUY-DOS and GT1 parasite strains. We report here that mouse susceptibility to secondary infection correlates with initial parasite burden and that protection to the RH strain is dependent on CD8 but not CD4 T cells in this model. When given a lethal secondary infection, CD8 and CD4 T cells upregulate several co-inhibitory receptors including PD-1, TIM-3, 4-1bb and CTLA-4. Moreover, CD8 but not CD4 T cells are significantly reduced in their IFNγ response during secondary infection with virulent strains, suggesting checkpoint blockade may reduce disease severity. However, single and combination therapies targeting TIM-3, CTLA-4, and/or PD-L1 failed to reverse susceptibility to secondary infection. These results suggest that additional host responses, which are refractory to checkpoint blockade, are likely required for immunity to this pathogen.

The IL-12– and IL-23–Dependent NK Cell Response Is Essential for Protective Immunity against Secondary Toxoplasma gondii Infection

“…Protection against secondary T. gondii infection is provided mainly by memory CD8 + T cells and was defined using vaccine and challenge approaches (38,64,65). How other immune cells, including NK cells, might contribute to this protection has not been clear.…”

The IL-12– and IL-23–Dependent NK-Cell Response is Essential for Protective Immunity Against SecondaryToxoplasma GondiiInfection

“…Protection against secondary T. gondii infection is provided mainly by memory CD8+ T cells and was defined using vaccine and challenge approaches (35, 63, 64). How other immune cells, including NK cells, might contribute to this protection has not been clear.…”

Nfkbidis required for immunity and antibody responses toToxoplasma gondii

“…PECs were isolated by peritoneal lavage and splenocytes obtained, as described in [26]. In brief, 4mL of FACS buffer (PBS with 1% FBS) and 3mL of air were injected into the peritoneal cavity with a 27G needle.…”

“…“superinfect”) the brains of challenged survivors [25]. During secondary infection memory CD8 T cells become exhausted, but checkpoint blockade fails to reverse disease outcome [26]. The data suggest yet unknown mechanisms are needed to provide heterologous immunity to highly virulent strains of T. gondii .…”