| Summary: | <p>CD1a has been demonstrated to contribute to anti-bacterial immune responses
by presenting lipid antigens to T cells. Skin Staphylococcus aureus (S. aureus)
colonization has been documented to be strongly associated with the severity of
skin inflammatory diseases including atopic dermatitis (AD). However, there have
been limited studies of how the bacterial colonization contributes to pathology
and exacerbation of disease.</p>
<p>Here, we investigate the involvement of a S. aureus exotoxin, sphingomyelinase
(SMase), in regulating T cell immune responses via CD1a. We show that SMase
enzymatic activity plays an essential role in CD1a-reactive T cell activation in both
peripheral blood and skin, leading to production of inflammatory cytokines,
including IFNγ, IL-17A, and IL-22. These findings support the possibility that the
ceramide product of SMase may serve as a permissive lipid neoantigen and that
SMase may reduce the non-permissive effects of sphingomyelin. Patients with
atopic dermatitis had reduced CD1a-dependent IFNγ responses to SMase
compared to healthy controls.</p>
<p>The generation of CD1a-reactive SMase-specific T cell lines and clones facilitated
the further study of mechanisms underlying CD1a antigen presentation, including
the novel identification of a Vγ9/Vδ2 CD1a-autoreactive T cell clone which
expanded our understanding of CD1a-reactive T cell repertoire and potential
pathways of gamma-delta T cell activation. The work also identified that CD1a
may be a marker of activation of peripheral T cells.</p>
<p>In conclusion, we have discovered a previously unrecognized pathway of
inflammation where SMase derived from S. aureus can modulate CD1a ligands
which are presented to lipid-specific T cells.</p>
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