Staphylococcus aureus Infection of Mice Expands a Population of Memory γδ T Cells That Are Protective against Subsequent Infection

Abstract

The development of vaccines against S. aureus has consistently failed in clinical trials, likely due to inefficient induction of cellular immunity. T cell-derived IL-17 is one of the few known correlates of anti-staphyloccoal immunity, conferring protection against S. aureus infections through its ability to promote phagocytic cell effector functions. A comprehensive understanding of the discrete T cell subsets critical for site-specific IL-17-mediated bacterial clearance will therefore be necessary to inform the development of vaccines that efficiently target cellular immunity. In this study, we have identified a population of CD44+CD27− memory γδ T cells, expanded upon infection of C57BL/6 mice with S. aureus, which produce high levels of IL-17 and mediate enhanced bacterial clearance upon re-infection with the bacterium. These cells are comprised largely of the Vγ4+ subset and accumulate at the site of infection subsequent to an initial Vγ1.1+ and Vγ2+ T cell response. Moreover, these Vγ4+ T cells are retained in the peritoneum and draining mediastinal lymph nodes for a prolonged period following bacterial clearance. In contrast to its critical requirement for γδ T cell activation during the primary infection, IL-1 signalling was dispensable for activation and expansion of memory γδ T cells upon re-exposure to S. aureus. Our findings demonstrate that a γδ T cell memory response can be induced upon exposure to S. aureus, in a fashion analogous to that associated with classical αβ T cells, and suggest that induction of IL-17-expressing γδ T cells may be an important property of a protective vaccine against S. aureus.

Inflammation induces dermal Vγ4 + γδT17 memory-like cells that travel to distant skin and accelerate secondary IL-17–driven responses

“…In another study, peritoneal infection with Staphylococcus aureus led to the persistence of an expanded population of Vγ6 + γδT cells. Again the expanded cells showed restricted tissue tropism, persisting in the peritoneum and draining LNs (22). Our findings for Vγ4 + Vδ4 + cells provide further evidence for the ability of γδT cells to acquire memory characteristics including accelerated activation and proliferation after reencountering a stimulus.…”

“…Memory responses are a defining feature of the conventional αβT-cell compartment, yet whether γδT cells develop immune memory has been investigated less. Recent studies of Vγ6 + intestinal and peritoneal cells have begun to provide support for γδT-cell memory responses (21,22). However, it is not yet clear whether dermal γδT17 cells can take on memory characteristics.…”

IL-10 Plays Opposing Roles during Staphylococcus aureus Systemic and Localized Infections

“…Collectively, our current data demonstrate a clear role for IL-10 in controlling T cell and phagocyte activation, which subsequently dictates disease outcome during two contrasting S. aureus infection types. Previously published data have now demonstrated that cellular responses, including Th1, Th17, and gd + T cell responses, are all involved in the host defense against S. aureus infections (30,32,34,40); however, their relative prominence varies depending on whether the infection is local or systemic, the anatomical site of the local infection, and whether the infection is acute or chronic. As the skin is the largest organ of the body and an important barrier against invading bacteria, it comprises a complex immune system involving DCs, keratinocytes, T cells, and regulatory B cells that create a tolerant microenvironment to prevent undesirable inflammation in response to commensal organisms (41,42).…”

“…In particular, we demonstrate that IL-10 acts upstream of effector T cells, controlling their cytokine responses. We have previously shown that gd-derived IL-17 and type I immune responses are required at different stages of S. aureus peritoneal infection to promote effective bacterial clearance through the ability of these cytokines to regulate downstream phagocyte responses (30,32). However, it appears that these T cell responses cannot be allowed to proceed unchecked and that effective resolution of infection requires the gd + T cell and CD4 + T cell responses to be tightly controlled so as to avoid host pathology that would ensue from excessive phagocyte activation.…”

“…We and others have previously demonstrated important protective roles for IL-17-producing gd + T cells and IFN-g-producing Th1 cells during S. aureus infection through the ability of these cytokines to regulate the recruitment and activation of both neutrophils and macrophages, respectively (30,32). To ascertain whether IL-10 acts upstream to regulate the effects of these T cells, T cell activation and associated phagocytic cell responses were assessed within the peritoneal cavity at specific time points postinfection in WT and IL-10 2/2 mice.…”