Abstract
Staphylococcus aureus (SA) is the causative agent of both skin/soft tissue infections as well as invasive bloodstream infections. Though vaccines have been developed to target both humoral and T cell-mediated immune responses against SA, they have largely failed due to lack of protective efficacy. Group 1 CD1-restricted T cells recognize lipid rather than peptide antigens. Previously found to recognize lipids derived from cell wall of Mycobacterium tuberculosis (Mtb), these cells were associated with protection against Mtb infection in humans. Using a transgenic mouse model expressing human group 1 CD1 molecules (hCD1Tg), we demonstrate that group 1 CD1-restricted T cells can recognize SA-derived lipids in both immunization and infection settings. Systemic infection of hCD1Tg mice showed that SA-specific group 1 CD1-restricted T cell response peaked at 10 days post-infection, and hCD1Tg mice displayed significantly decreased kidney pathology at this time point compared with WT control mice. Immunodominant SA lipid antigens recognized by group 1 CD1-restricted T cells were comprised mainly of cardiolipin and phosphatidyl glycerol, with little contribution from lysyl-phosphatidyl glycerol which is a unique bacterial lipid not present in mammals. Group 1 CD1-restricted T cell lines specific for SA lipids also conferred protection against SA infection in the kidney after adoptive transfer. They were further able to effectively control SA replication in vitro through direct antigen presentation by group 1 CD1-expressing BMDCs. Together, our data demonstrate a previously unknown role for group 1 CD1-restricted SA lipid-specific T cells in the control of systemic MRSA infection.
Highlights
Staphylococcus aureus (SA) is one of the most frequently isolated pathogens associated with nosocomial infections [1]
Group 1 CD1-restricted T cells in SA infection lipid-reactive T cell subset has never been studied in the context of systemic SA infection, and investigating their contribution to SA host defense could be fruitful in anti-SA vaccine design
Using a mouse model expressing group 1 CD1 molecules, we show that these T cells recognize and are activated by SA lipids during immunization and infection
Summary
Staphylococcus aureus (SA) is one of the most frequently isolated pathogens associated with nosocomial infections [1]. One study identified a CD4+ T cell epitope from the SA heme-uptake protein IsdB able to induce proliferation and IFN-γ and IL-17 secretion from T cells [16]. Another group identified the epitope M8 derived from manganese transport protein C (MntC) to induce proliferation and IL-17 secretion from CD4+ T cells in immunized BALB/ c mice [17]. Recent studies have found a clonal Vγ6+Vδ4+ T cell subset secreting IL-17 to be crucial for protective immunity against SA skin infection in mice [22]. Despite data showing the importance of conventional CD4+ T cells and γδ T cells to defense against SA, the role of lipid antigen-specific group 1 CD1-restricted T cells remains unexplored
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