CD1a-autoreactive T cells are increasingly being implicated in the pathogenesis of inflammatory skin diseases including dermatitis and psoriasis. Human CD1a-autoreactive T cell clones were isolated from individuals with disease and healthy controls, in order to investigate functionality in relation to ex vivo phenotype. The T cells produced diverse cytokines, but with a notable type 2 bias. TCRs transferred using CRISPR-mediated orthotopic replacement confirmed TCR reactivity to CD1a housing endogenous small or headless lipids such as lysophosphatidylcholine, as well as frequent inhibition by very long chain sphingomyelins. Having designed, synthesized and investigated synthetic CD1a-blocking sphingomyelin analogues for CD1a inhibition in vitro, their efficacy was tested in models of skin inflammation using humanised CD1a in vivo transgenesis. An unexpected role was found for CD1a in pruritus, in part mediated by TSLP. The sphingomyelin analogues strongly and significantly inhibited MC903-induced pruritus and associated type 2 skin inflammation. Collectively these data point to non-redundant roles of CD1a in skin disease manifestation in vivo and that modulation of CD1a presentation may have therapeutic utility.