Donor Unrestricted T Cells: A Shared Human T Cell Response

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.

Figure 1. Polymorphic and non-polymorphic antigen presenting molecules stimulate different kinds of TCR repertoires

For two genetically unrelated persons, the number of αβ TCR pairs defined as unique amino acid sequences (dots) represent a small fraction of all possible TCRs (6, 8, 10, 11). In the MHC system, interdonor TCR diversity is high and two unrelated donors have mostly private TCRs that differ in TCR α and β chain pairing (8, 12) (A). Invariant TCRs on invariant NKT cells (iNKT), mucosa-associated invariant T cells (MAIT), germline-encoded mycolyl-reactive (GEM) T cells and LDN5-like T cells are genetically unrestricted T cell types that show low interdonor diversity. In addition 16 TCRs of unknown antigen specificity are conserved among more than 50 percent of human donors, representing candidate invariant TCRs (51)(grey) (B).

Figure 2. The distribution of MHC-restricted public TCRs is limited by the allele frequency of the antigen presenting molecule

Expression of allelic variants of MHC encoded antigen presenting molecules is limited to small human subpopulations, and so are the public T cells that recognize these molecules (60-67). CD1 and MR1 genes are expressed similarly in nearly 100 percent of humans, so T cells that recognize CD1 or MR1 can be considered donor unrestricted (17, 43, 44, 68). Allele frequency datasets were obtained from www.allelefrequencies.net. African American: USA NMDP African American n=416,581; Caucasian: USA NMDP European Caucasean n=1,242,890; Chinese: USA NMDP Chinese n=99,672. *Single nucleotide polymorphisms are known (3), but functionally distinct alleles of CD1 and MR1 molecules have not been discovered. Individuals with low or high expression levels of CD1a on their dendritic cells have been described (4). **For each viral protein antigen that is recognized by public TCRs, the location of the peptide epitope is shown in brackets.