How an alloreactive T-cell receptor achieves peptide and MHC specificity

Abstract

T-cell receptor (TCR) allorecognition is often presumed to be relatively nonspecific, attributable to either a TCR focus on exposed major histocompatibility complex (MHC) polymorphisms or the degenerate recognition of allopeptides. However, paradoxically, alloreactivity can proceed with high peptide and MHC specificity. Although the underlying mechanisms remain unclear, the existence of highly specific alloreactive TCRs has led to their use as immunotherapeutics that can circumvent central tolerance and limit graft-versus-host disease. Here, we show how an alloreactive TCR achieves peptide and MHC specificity. The HCV1406 TCR was cloned from T cells that expanded when a hepatitis C virus (HCV)-infected HLA-A2 − individual received an HLA-A2 + liver allograft. HCV1406 was subsequently shown to recognize the HCV nonstructural protein 3 (NS3):1406-1415 epitope with high specificity when presented by HLA-A2. We show that NS3/HLA-A2 recognition by the HCV1406 TCR is critically dependent on features unique to both the allo-MHC and the NS3 epitope. We also find cooperativity between structural mimicry and a crucial peptide "hot spot" and demonstrate its role, along with the MHC, in directing the specificity of allorecognition. Our results help explain the paradox of specificity in alloreactive TCRs and have implications for their use in immunotherapy and related efforts to manipulate TCR recognition, as well as alloreactivity in general.T-cell receptor | peptide-MHC | structure | alloreactivity | specificity

Emerging Concepts in TCR Specificity: Rationalizing and (Maybe) Predicting Outcomes

“…Some of these examples are summarized in a recent analysis of several structures (32). In some cases, germline-encoded CDR1 loops interface with the N-terminal or C-terminal halves of peptides, contributing to peptide specificity (33–35). Conformations of neighboring CDR loops can influence one another (36–38).…”

“…In another case, the Mel5 TCR forms a specificity-determining salt-bridge with Glu1 of the MART-1 26-35 peptide using the germline CDR1α loop (33, 34). The HCV1406 TCR which recognizes the HCV NS3 epitope requires a lysine at P1, which is also engaged by CDR1α (35). Lastly, the flexibility inherent to some TCRs (65) may permit different hot spots with different ligands, as is believed to occur the well-studied TCR 2C (66, 67).…”

“…More recently, the properties of the alloreactive TCR HCV1406 were studied (35). The HCV1406 TCR was identified from T cells that expanded when a HLA-A2+ liver was transplanted into a HCV-infected HLA-A2- host (87).…”

“…The HCV1406 TCR was identified from T cells that expanded when a HLA-A2+ liver was transplanted into a HCV-infected HLA-A2- host (87). T cells expressing HCV1406 mediated anti-HCV immunity, specifically targeting the HCV NS3 antigen presented by HLA-A2 (35). Again, TCR binding was found to be dependent on features unique to both the peptide and the foreign MHC.…”

“…We suggest that in addition to explaining specificity in alloreactivity, these same principles can help explain the high frequencies of alloreactive T cells. The combination of unique peptides, unique modes of presentation, and different features on MHC α helices provides for composite recognition surfaces very distinct from those TCRs encounter syngeneically (35). In alloreactivity, TCRs indeed see something new – but it is not only peptide or MHC, but their synergistic combination that results in significant T cell reactivity.…”