In collaboration with Vincenzo Cerundolo and Branch Moody, we have recently shown that bee and wasp venom phospholipase generates neolipid antigens for presentation by CD1a in skin from healthy individuals.  In order to investigate the relevance to clinical disease, we have defined the frequency and phenotype of phospholipase-responsive CD1a-reactive T cells in cohorts of patients with allergic disease.  Venom allergic individuals showed significantly higher frequencies of IFN-γ, GM-CSF and IL-13 producing CD1a-reactive T cells responsive to whole venom and venom-derived phospholipase than healthy individuals. CD1a-reactive T cells were cross-responsive between wasp venom, bee venom and bee venom phospholipase, suggesting shared pathways of allergenicity.  We have also followed patients through allergen immunotherapy, in which venom is delivered subcutaneously at progressively increasing doses and associates with clinical tolerance induction.  Venom-responsive CD1a-reactive T cells initially increase during immunotherapy, but despite dose escalation of administered antigen the T cells subsequently reduce in frequency as the patients become tolerant.  Overall these data support a role for phospholipase-responsive CD1a-reactive T cells in the venom allergic process.