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

Although recent studies have indicated that the major histocompatibility complex-like, beta 2-microglobulin-associated CD1 molecules might function to present a novel chemical class of antigens, lipids and glycolipids, to alpha/beta T cells, little is known about the T cell subsets that interact with CD1. A subset of CD1d-autoreactive, natural killer (NK)1.1 receptor-expressing alpha/beta T cells has recently been identified. These cells, which include both CD4(-)CD8(-) and CD4(+) T cells, preferentially use all invariant V alpha 14-J alpha 281 T cell receptor (TCR) of chain paired with a V beta 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 as interleukin (IL)-4 and interferon (IFN)-gamma upon TCR engagement and may regulate a variety of infectious and autoimmune conditions. Here, we report the existence of a second subset of CD1d-restricted CD4(+) T cells that do 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 autoreactivity 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 presentation. Antigen presentation to the V alpha 14(+) NK1.1(+) cells requires 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 subsets of CD1d-restricted T cells that survey self-antigens loaded in distinct cellular compartments.