Distinct subsets of CD1d-restricted T cells recognize self-antigens loadedin different cellular compartments

Although recent studies have indicated that the major histocompatibility co mplex-like, beta 2-microglobulin-associated CD1 molecules might function to present a novel chemical class of antigens, lipids and glycolipids, to alp ha/beta T cells, little is known about the T cell subsets that interact wit h CD1. A subset of CD1d-autoreactive, natural killer (NK)1.1 receptor-expre ssing alpha/beta T cells has recently been identified. These cells, which i nclude both CD4(-)CD8(-) and CD4(+) T cells, preferentially use all invaria nt V alpha 14-J alpha 281 T cell receptor (TCR) oi chain paired with a V be ta 8 TCR beta chain in mice, or the homologous V alpha 24-J alpha Q/V beta 11 in humans. This cell subset can explosively release key cytokines such a s interleukin (IL)-4 and interferon (IFN)-gamma upon TCR engagement and may regulate a variety of infectious and autoimmune conditions. Here, we repor t the existence of a second subset of CD1d-restricted CD4(+) T cells that d o not express the NK1.1 receptor or the V alpha 14 TCR Like the V alpha 14( +) NK1.1(+) T cells, these T cells exhibit a high frequency of autoreactivi ty to CD1d, use a restricted albeit distinct set of TCR gene families, and contribute to the early burst of IL-4 and IFN-gamma induced by intravenous injection of anti-CD3. However, the V alpha 14(+) NK1.1(+) and V alpha 14(- ) NK1.1(-) T cells differ markedly in their requirements for self-antigen p resentation. Antigen presentation to the V alpha 14(+) NK1.1(+) cells requi res endosomal targeting of CD1d through a tail-encoded tyrosine-based motif , whereas antigen presentation to the V alpha 14(-) NK1.1(-) cells does not . These experiments suggest the existence of two phenotypically different s ubsets of CD1d-restricted T cells that survey self-antigens loaded ill dist inct cellular compartments.