CD1a-autoreactive T cells are abundant in human skin, accounting for up to ~25% of cutaneous T cells in some healthy donors. Increased frequencies of CD1a-autoreactive T cells are present in affected skin from both psoriasis and atopic dermatitis lesions; and human skin allergen challenge induces rapid infiltration of CD1a-autoreactive T cells. Tissue single cell analyses confirm diverse TCR expression and functionality, with orthotopic TCR replacement conferring CD1a reactivity in recipient T cells. However, whilst these data provide strong supporting evidence, they do not prove a causal role in disease. Here, we use different humanised in vivo models of type 2 and type 17 inflammation to show efficacy of blockade and/or depletion of CD1a-expressing cells in controlling inflammatory responses. Depletion of CD1a-expressing cells could be enhanced in the presence of bispecific T cell engagement, with associated implications for control of CD1a-expressing malignancies. Collectively these data add further support to the role of CD1a in disease and that depletion of CD1a-expressing cells may have dual utility in inflammation and malignancy.