Abstract
NK cells regulate CD4+ and CD8+ T cells in acute viral infection, vaccination, and the tumor microenvironment. NK cells also become exhausted in chronic activation settings. The mechanisms causing these ILC responses and their impact on adaptive immunity are unclear. CD8+ T cell exhaustion develops during chronic Toxoplasma gondii (T. gondii) infection resulting in parasite reactivation and death. How chronic T. gondii infection impacts the NK cell compartment is not known. We demonstrate that NK cells do not exhibit hallmarks of exhaustion. Their numbers are stable and they do not express high PD1 or LAG3. NK cell depletion with anti-NK1.1 is therapeutic and rescues chronic T. gondii infected mice from CD8+ T cell exhaustion dependent death, increases survival after lethal secondary challenge and alters cyst burdens in brain. Anti-NK1.1 treatment increased polyfunctional CD8+ T cell responses in spleen and brain and reduced CD8+ T cell apoptosis in spleen. Chronic T. gondii infection promotes the development of a modified NK cell compartment, which does not exhibit normal NK cell characteristics. NK cells are Ly49 and TRAIL negative and are enriched for expression of CD94/NKG2A and KLRG1. These NK cells are found in both spleen and brain. They do not produce IFNγ, are IL-10 negative, do not increase PDL1 expression, but do increase CD107a on their surface. Based on the NK cell receptor phenotype we observed NKp46 and CD94-NKG2A cognate ligands were measured. Activating NKp46 (NCR1-ligand) ligand increased and NKG2A ligand Qa-1b expression was reduced on CD8+ T cells. Blockade of NKp46 rescued the chronically infected mice from death and reduced the number of NKG2A+ cells. Immunization with a single dose non-persistent 100% protective T. gondii vaccination did not induce this cell population in the spleen, suggesting persistent infection is essential for their development. We hypothesize chronic T. gondii infection induces an NKp46 dependent modified NK cell population that reduces functional CD8+ T cells to promote persistent parasite infection in the brain. NK cell targeted therapies could enhance immunity in people with chronic infections, chronic inflammation and cancer.
Highlights
Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan that is the 3rd leading cause of foodborne illness in the U.S (Mead et al, 1999) At least one-third of the human population is infected with this parasite and it is a major health concern for people who become immune compromised and in the developing fetus (Harms Pritchard et al, 2015; Gigley, 2016)
To further dissect the immune mechanisms contributing to T cell exhaustion during chronic T. gondii infection, we investigated the role of innate lymphoid cells and NK cells
Based on the ability of NK cells to contribute to immunity after the innate response is over and their potential to develop immune exhaustion we determined whether NK cells were still in abundance during late chronic T. gondii infection and their immune exhaustion status
Summary
Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan that is the 3rd leading cause of foodborne illness in the U.S (Mead et al, 1999) At least one-third of the human population is infected with this parasite and it is a major health concern for people who become immune compromised and in the developing fetus (Harms Pritchard et al, 2015; Gigley, 2016). T. gondii infection induces a potent cell mediated response that is initiated by the production of IL-12 which helps activate CD8+ T cells to produce IFNγ (Suzuki and Remington, 1988; Suzuki et al, 1988; Gazzinelli et al, 1994a,b). CD8+ T cell IFNγ production is the major mediator of this infection. Despite induction of a robust Th1 response, the parasite is never cleared. The immunological reason why this infection is not cleared is still unknown
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