NK cells negatively regulate CD8 T cells to promote immune exhaustion and chronic Toxoplasma gondii infection

Abstract

Abstract Previous studies demonstrate CD8 T cell immune exhaustion is a major factor in promoting chronic Toxoplasma gondii (T. gondii) infection. How other immune cells are impacted by chronic T. gondii infection to promote CD8 T cell exhaustion and chronic parasite infection are not known. We investigated natural killer cells (NK cells) and how they contribute to chronic Toxoplasmosis. We find NK cells are not exhausted because NK cell numbers do not decrease during late stage infection and do not up regulate PD-1 or LAG3. NK cells in chronic parasite infection have reduced IFNγ, do not produce IL-10 or increase their expression of PD-L1, however, they expressed elevated CD107a. We also find NK cells become more highly mature (KLRG1+) during chronic T. gondii infection. We conclude that they do not become exhausted as do CD8 T cells, but alter their function during chronic T. gondii infection. Importantly, we demonstrate NK cell depletion with anti-NK1.1 is therapeutic and rescues mice from death normally caused by CD8 T cell exhaustion and parasite reactivation. This treatment reduced CD8 T cell apoptosis, increased parasite specific polyfunctional CD8 T cell responses and prevented parasite reactivation. NKp46+ NK cells were enriched for expression of CD94 and NKG2A. NKp46 ligand and Qa-1b expression were altered to promote enrichment of this specific NK cell population. Blockade with anti-NKp46 also rescued the mice from death associated with exhausted CD8 T cells and parasite reactivation. We hypothesize NK cells via NKp46 significantly contribute to promoting chronic T. gondii infection. Understanding how NK cells develop this response will improve therapies for individuals at risk for reactivation of chronic infections.