Abstract
The now-famous term "restriction" derived from experiments in which T cells from Donor A failed to recognize Ags presented by cells from Donor B. Restriction results from interdonor variation in MHC genes. Donor restriction dominates immunologists' thinking about the T cell response because it governs organ transplantation and hinders the discovery of disease-associated Ags. However, other T cells can be considered "donor unrestricted" because their targets, CD1a, CD1b, CD1c, CD1d, or MR1, are expressed in a similar form among all humans. A striking feature of donor unrestricted T cells is the expression of invariant TCRs with nearly species-wide distribution. In this article, we review new evidence that donor unrestricted T cells are common in humans. NKT cells, mucosa-associated invariant T cells, and germline-encoded mycolyl-reactive T cells operate outside of the familiar principles of the MHC system, providing a broader picture of T cell function and new opportunities for therapy.