T Cells Engaging the Conserved MHC Class Ib Molecule Qa-1 with TAP-Independent Peptides Are Semi-Invariant Lymphocytes.

The HLA-E homolog in the mouse (Qa-1) 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-1-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.

T cells specific for a TAP-independent self-peptide remain naïve in tumor-bearing mice and are fully exploitable for therapy.

Cancers frequently evade immune-recognition by lowering peptide:MHC-I complexes on their cell surface. Limited peptide supply due to TAP-deficiency results in such MHC-I immune-escape variants. Previously, we reported on a category of TAP-independent self-peptides, called TEIPP, with selective presentation by these tumors.

TAP-independent self-peptides enhance T cell recognition of immune-escaped tumors.

Tumor cells frequently escape from CD8+ T cell recognition by abrogating MHC-I antigen presentation. Deficiency in processing components, like the transporter associated with antigen processing (TAP), results in strongly decreased surface display of peptide/MHC-I complexes. We previously identified a class of hidden self-antigens known as T cell epitopes associated with impaired peptide processing (TEIPP), which emerge on tumor cells with such processing defects.