Abstract
MHC-independent αβTCRs (TCRs) recognize conformational epitopes on native self-proteins and arise in mice lacking both MHC and CD4/CD8 coreceptor proteins. Although naturally generated in the thymus, these TCRs resemble re-engineered therapeutic chimeric antigen receptor (CAR) T cells in their specificity for MHC-independent ligands. Here we identify naturally arising MHC-independent TCRs reactive to three native self-proteins (CD48, CD102, and CD155) involved in cell adhesion. We report that naturally arising MHC-independent TCRs require high affinity TCR-ligand engagements in the thymus to signal positive selection and that high affinity positive selection generates a peripheral TCR repertoire with limited diversity and increased self-reactivity. We conclude that the affinity of TCR-ligand engagements required to signal positive selection in the thymus inversely determines the diversity and self-tolerance of the mature TCR repertoire that is selected.
Highlights
The ligand recognition specificity of the αβT cell receptor (TCR) repertoire is established during T cell differentiation in the thymus
We generated T-hybridomas from QB Lymph node αβT (LNT) cells that had been stimulated with platebound anti-TCRβ/anti-CD28 antibodies and screened them for recognition of Major Histocompatibility Complex (MHC)-independent ligands expressed on MHCKO antigen presenting cells (APCs) (Figure 1A)
The present study reveals that MHC-independent TCRs require high affinity TCR-ligand engagements to signal positive selection and that high affinity positive selection generates a mature repertoire with increased self-reactivity and markedly reduced TCR diversity
Summary
The ligand recognition specificity of the αβT cell receptor (TCR) repertoire is established during T cell differentiation in the thymus. The recombination activating genes Rag and Rag induce random TCR gene re-arrangements in immature thymocytes and those with productively rearranged TCRα and TCRβ genes express αβTCR protein complexes on their cell surfaces [1]. These randomly generated surface αβTCR complexes constitute the pre-selection TCR repertoire and display a huge diversity of potential ligand recognition specificities from which the mature TCR repertoire is selected in the thymus [2]. Immature thymocytes whose TCRs successfully engage an intra-thymic ligand generate TCR-mediated survival signals and differentiate into mature T cells, events referred to as positive selection [3, 4].
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