Abstract
The HLA-E homolog in the mouse (Qa-1b) is a conserved MHC class Ib molecule presenting monomorphic peptides to germline-encoded natural killer receptor CD94/NKG2A. Previously, we demonstrated the replacement of this canonical peptide by a diverse peptidome upon deficiency of the TAP peptide transporter. Analysis of this Qa-1b-restricted T cell repertoire against these non-mutated neoantigens revealed characteristics of conventional hypervariable CD8+ T cells, but also of invariant T cell receptor (TCR)αβ T cells. A shared TCR Vα chain was used by this subset in combination with a variety of Vβ chains. The TCRs target peptide ligands that are conserved between mouse and man, like the identified peptide derived from the transcriptional cofactor Med15. The thymus selection was studied in a TCR-transgenic mouse and emerging naïve CD8+ T cells displayed a slightly activated phenotype, as witnessed by higher CD122 and Ly6C expression. Moreover, the Qa-1b protein was dispensable for thymus selection. Importantly, no self-reactivity was observed as reported for other MHC class Ib-restricted subsets. Naïve Qa-1b restricted T cells expanded, contracted, and formed memory cells in vivo upon peptide vaccination in a similar manner as conventional CD8+ T cells. Based on these data, the Qa-1b restricted T cell subset might be positioned closest to conventional CD8+ T cells of all MHC class Ib populations.
Highlights
The non-classical mouse MHC class I (MHC-I) molecule Qa-1b and its human homolog HLA-E are non-polymorphic MHC molecules with important functions in innate immunity
We studied common characteristics of Qa-1b-restricted T cells that recognize these alternative peptides on TAP-deficient target cells. We demonstrate that these T lymphocytes display features of semi-invariant T cells: 1. a conserved T cell receptor (TCR) Vα segment is used, whereas their CDR3 and the TCRβ chains were diverse; 2. the Qa-1b presented peptide ligands were shared by mouse, human, and monkey cells; 3. the generation in the thymus was inefficient in a TCR-transgenic mouse, and 4. the thymus education was independent of Qa-1b
Limited TCR Vα diversity was recently described for Qa-1b-restricted T lymphocytes specific for ERAAP-deficient target cells, another Vα usage was reported for these CD8+ T cells [32]
Summary
The non-classical mouse MHC class I (MHC-I) molecule Qa-1b and its human homolog HLA-E are non-polymorphic MHC molecules with important functions in innate immunity These proteins bind and present signal peptides of classical MHC-I molecules at the cell surface and, as such, act as indirect sensors for the normal expression of MHC-I molecules [1, 2]. The Qdm/Qa-1b complex serves as a ligand for the germ-line encoded heterodimeric CD94/NKG2A receptors expressed on NK cells and activated CD8+ T cells and transduces inhibitory signals to these lymphocytes [5,6,7] This innate role of Qa-1b and HLA-E has been well characterized.
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