Natural venoms are high potency toxins with complex mechanisms of action. In The Journal of Experimental Medicine, Bourgeois et al. show that the human T cell repertoire contains T cell clones that react to bee and wasp venom in a manner dependent on the antigen-presenting molecule CD1a. Skin dendritic cells and Langerhans cells, which have high CD1a expression, can prime these responses. Venom fractionation indicates that the venom does not directly provide a lipid antigen but that venom-derived phospholipases such as PLA2 cleave intact, non-antigenic phospholipids into antigenic fatty acids, which activate CD1a-reactive T cells. Injection of wasp or bee venom (at concentrations that mimic a sting) changes the lipid content of the skin to generate fatty acids that can be predicted by the enzymatic specificity of PLA2, and neutralization of PLA2 blocks CD1a-specific T cell reactivity. This indicates that PLA2 is the essential venom compound for the generation of CD1a ligands.

J. Exp. Med. (12 January 2015) doi:10.1084/jem.20141505