While most T cells recognize peptide antigens presented by major histocompatibility complex (MHC) class I and class II molecules, some T cells react with lipid antigens presented by MHC-related CD1 proteins. In this issue, Bourgeois et al. establish the concept that enzymes in bee venom can cleave host skin-derived phospholipids into lipid neoantigens that activate CD1a-restricted T cells to promote a local inflammatory response.

Humans have four CD1 proteins: CD1a, CD1b, CD1c, and CD1d. The CD1a molecule has long been known as a specific surface marker for human Langerhans cells, and recent studies have shown that CD1a-restricted T cells are recruited to the skin. Such T cells are intrinsically autoreactive, recognizing skin-specific oils produced by sebaceous glands.

In searching for potential contributions of CD1a-reactive T cells to inflammatory responses in the skin, Bourgeois et al. investigated human T cell responses to the venoms of bees and wasps. They found that such venoms induce a CD1a-mediated response in both individual T cell clones and primary human T cells. However, further analyses revealed that the antigenic substance unexpectedly partitioned within the lipid rather than the protein fractions, raising the possibility that enzymes in the venom generate lipid antigens by cleaving common phospholipids. The investigators were able to zoom in on phospholipase A2 (PLA2), an enzyme that is abundant in insect and snake venoms, which acts on phospholipids to release fatty acids and lysophospholipids.

These intriguing findings support a model of T cell activation involving insect-mediated PLA2 introduction into the skin, inducing the release of fatty acid neoantigens from common skin phospholipids, subsequently sampled by Langerhans cells, loaded onto CD1a molecules, and presented to T cells. Activated CD1a-reactive T cells produce IL-22, a cytokine that plays a role in antimicrobial defenses, promotes keratinocyte proliferation, and contributes to the pathogenesis of a variety of skin inflammatory diseases. In this manner, CD1a-reactive T cells may contribute to the local inflammatory response to venoms. The findings also provide a potential molecular explanation for the generation of autoantigens in normal skin, which expresses secreted phospholipases. It has been proposed that such natural lipids are present at the surface of the skin and are thus inaccessible to CD1a-restricted T cells in the dermis. However, a breach in the skin barrier might make these natural oils available to Langerhans cells in the epidermis, resulting in their presentation to CD1a-reactive T cells and the subsequent induction of antimicrobial and inflammatory responses. Moreover, infections and inflammatory processes can modulate the expression patterns of phospholipases in the skin, which may represent a mechanism to control inflammation via CD1a-reactive T cells. Finally, certain skin pathogens secrete PLA2 enzymes, raising the possibility that such infections can induce CD1a-mediated T cell responses that contribute to host immunity and disease pathogenesis. These proposed scenarios, together with their potential therapeutic applications, will provide rich and fertile avenues for future investigation.

References

References
Bourgeois
,
E.A.
, et al
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2015
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J. Exp. Med.
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