Innate-Like T Cells in Systemic Methicillin-Resistant Staphylococcus aureus Infection

Genardi, Samantha Marie

doi:https://doi.org/10.21985/n2-rnre-tb49

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Innate-Like T Cells in Systemic Methicillin-Resistant Staphylococcus aureus Infection

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Staphylococcus aureus (SA) is a leading cause of healthcare-associated and community-acquired infection in the United States. Despite the canonical thinking that antibodies and B cells are the main drivers of protection against extracellular pathogens, T cells are now recognized as critical players in protection against SA in multiple routes of infection, as evidenced in humans and preclinical animal models. Patients with CD4+ T cell HIV-mediated depletion or genetic deficiency in Th17 cell development have increased susceptibility to SA infections. In mouse models of SA infection, both CD4+ T cells and gamma delta T cells have been implicated in cytokine production and protection against SA, driven by IFN-g and IL-17A. Additionally, gamma delta T cell memory has been described in both humans and mice and played a protective role in a mouse model of SA skin infection. Unconventional T cells, which are not restricted by major histocompatibility complex (MHC) class I or class II molecules, have emerged as critical players in the immune response to bacterial infections. Here I studied the roles of 2 types of unconventional T cells, natural killer T (NKT) cells and mucosal-associated invariant T (MAIT) cells, in the context of methicillin-resistant SA infection. These innate-like T cells can be activated very early during bacterial infection and secrete Th1 and Th17 cytokines. NKT cells are restricted by the MHC class I-like molecule CD1. CD1 molecules present lipid antigens to cognate T cells and have limited polymorphism relative to their MHC counterparts, making them attractive vaccine targets. MAIT cells are restricted by the MHC class Ib molecule MR1, which presents vitamin B metabolites to MAIT cells. Many bacteria, including SA, possess metabolic proteins that generate metabolites able to be recognized by MAIT cells, making MAIT cells an additional target for rational vaccine design. To determine whether NKT cells or MAIT cells were necessary for controlling SA infection, I infected wild-type mice and mice deficient in NKT cells (CD1d-/-) or MAIT cells (MR1-/-) with SA. I showed that NKT cells, but not MAIT cells, were necessary for reducing bacterial burdens and controlling the amount of neutrophil influx to infected kidneys and livers early in the infection response. Using a mouse model that lacks type I NKT cells (iNKT cells) but retains type II NKT cells (Ja18-/-), I further showed that type II NKT cells were sufficient to reduce bacterial burden and inflammatory infiltrate/abscess dissemination in infected kidneys in the absence of iNKT cells. Both iNKT cells and type II NKT cells required MyD88 mediated TLR activation on dendritic cells and CD1d-TCR engagement to be activated by total SA lipids and heat-killed SA (HKSA), which demonstrated that innate-mediated cytokines as well as TCR engagement were required for NKT cell activation and cytokine production to SA antigens. However, iNKT cells were dispensable for control of SA infection and became hyporesponsive to restimulation after SA infection. Focusing on the role of type II NKT cells in SA infection, I identified a polar lipid fraction from SA containing PG and lysyl-PG species which induced CD1d-restricted MyD88-dependent IFN-g production by type II NKT cells. Adoptively transferred type II NKT cells directly contributed to a reduction in bacterial burden in the spleen of SA-infected recipient mice. Turning to humans, SA bacteremic patients had reduced percentages of MAIT cells and iNKT cells and increased CD4+CD161+ T cells, a population enriched for type II NKT cells, in blood compared to healthy controls. Work recently published by our lab, using humanized mice expressing group 1 CD1 molecules (hCD1Tg), showed that CD1b- and CD1c-restricted T cells were expanded after SA infection and recognized PG lipids derived from SA. Together, these data demonstrate that in mice and humans, both CD1d-restricted type II NKT cells and group 1 CD1-restricted T cells are expanded and functionally active during SA bacteremia.

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