Staphylococcus aureus infection of mice expands a population of memory γδ T cells that are protective against subsequent infection.

The development of vaccines against Staphylococcus 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 antistaphylococcoal 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 reinfection 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 signaling 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 αß 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.

Nlrp-3-driven interleukin 17 production by γδT cells controls infection outcomes during Staphylococcus aureus surgical site infection.

Recent work has identified T cells and the cytokines they produce as important correlates of immune protection during Staphylococcus aureus infections through the ability of these T cells to regulate local neutrophil responses. However, the specific T-cell subsets that are involved in coordinating protection at distinct sites of infection remains to be established. In this study, we identify for the first time an important role for γδT cells in controlling S. aureus surgical site infection (SSI). γδT cells are recruited to the wound site following S. aureus challenge, where they represent the primary source of interleukin 17 (IL-17), with a small contribution from other non-γδT cells. The IL-17 response is entirely dependent upon IL-1 receptor signaling. Using IL-17 receptor-deficient mice, we demonstrate that IL-17 is required to control bacterial clearance during S. aureus SSI. However, we demonstrate a strain-dependent requirement for γδT cells in this process due to the differential abilities of individual strains to activate IL-1ß production. IL-1ß processing relies upon activation of the Nlrp3 inflammasome complex, and we demonstrate that Nlrp3-deficient and IL-1 receptor-deficient mice have an impaired ability to control S. aureus SSI due to reduced production of IL-17 by γδT cells at the site of infection. Given that IL-17 has been identified as an important correlate of immune protection during S. aureus infection, it is vital that the unique cellular sources of this cytokine and mechanisms inducing its activation are identified at distinct sites of infection. Our study demonstrates that while IL-17 may be critically important for mediating immune protection during S. aureus SSI, the relative contribution of γδT cells to these protective effects may be strain dependent.

Preoperative neutrophil response as a predictive marker of clinical outcome following open heart surgery and the impact of leukocyte filtration.

OBJECTIVES: Open heart surgery is associated with a massive systemic inflammatory response. Neutrophils, are the main mediator of this response. We hypothesised that the degree of neutrophil activation and inflammatory response to open heart surgery varies individually and correlates with clinical outcome. The aim of this study was to determine if individual clinical outcome can be predicted preoperatively through assessment of in-vitro stimulated neutrophil responses. Following that, the effects of neutrophil depletion through leukocyte filters are examined. METHODS: Neutrophil responses were assessed preoperatively (n=40) through change in neutrophil adhesion molecule [CD11b, CD62L and P Selectin Glycoprotein-1 (PSGL-1)] expression before and after in-vitro stimulation with Phorbol 12-myristate 13-acetate, PMA (1 ng/ml), lipopolysaccharide, LPS (1 µg/ml) and N-Formyl-Met-Leu-Phe, fMLP (1 ng/ml). Stimulated neutrophil responses were then correlated with postoperative clinical outcome. Patients were then randomised to leukocyte filtration (n=20) and a control group (n=20) and the effect of leukocyte filtration on neutrophil response and clinical outcome were investigated. RESULTS: An individual variation in in-vitro stimulated neutrophil responses was demonstrated. Significant correlations were shown between neutrophil responses and maximum serum creatinine change, CKMB-fraction, adrenaline requirement, noradrenaline requirement, duration of adrenaline required and time to extubation. White cell count and percentage neutrophils were lower in the LD group (P=0.05). CD11b expression (P=0.005) and PSGL-1 expression (P=0.043) across leukocyte filters were also increased. However, no significant difference was detected in clinical outcome between the LD and control groups. CONCLUSION: Preoperative neutrophil responses to in-vitro stimuli can predict clinical outcome following open heart surgery. However, leukocyte filtration did not offer significant benefit in clinical outcome in our study.