The mouse CD1d-restricted repertoire is dominated by a few autoreactive T cell receptor families

To define the phenotype and T cell receptor (TCR) repertoire of CD1d-depend ent T cells, we compared the populations of T cells that persisted in major histocompatibility complex (MHC) deficient nice, which lack mainstream T c ells, with those from MHC/CD1d doubly deficient mice, which lack both mains tream and CD1d-dependent T cells. Surprisingly, up to 80% of the CD1d-depen dent T cells were stained by tetramers of CD1d/alpha -galactosylceramide, w hich specifically identify the previously described CD1d autoreactive V alp ha 14-J alpha 18/V beta8 natural killer (NK) T cells. Furthermore, zooming in on the CD1d-dependent non-V alpha 14 T cells, we found that, like V alph a 14 NK T cells, they mainly expressed recurrent, CD1d autoreactive TCR fam ilies and had a natural memory phenotype. Thus, CD1d-restricted T cells dif fer profoundly from MHC-peptide-specific T cells by their predominant use o f autoreactive and semiinvariant, rather than naive and diverse, TCRs. They more closely resemble other lineages of innate lymphocytes such as B-1 B c ells, gamma delta T cells, and NK cells, which express invariant or semiinv ariant autoreactive receptors. Finally, we demonstrate that the MHC-restric ted TCR repertoire is essentially non-cross-reactive to CD1d. Altogether, t hese findings imply that lipid recognition by CD1d-restricted T cells may h ave largely evolved as an innate rather than an adaptive arm of the mouse i mmune system.