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.
Highlights
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
In conflict with prevailing theories of T-cell alloreactivity, we show that the specific recognition of nonstructural protein 3 (NS3)/HLA-A2 by HCV1406 is dependent upon three intertwined components: the unique TCR contact surface of A2, including polymorphisms that distinguish it from the other MHC proteins present in the host; the impact of A2 polymorphisms on NS3 peptide binding and conformation; and unique structural and chemical features of the NS3 peptide
The drivers of TCR alloreactivity have been variously attributed to a TCR focus on unique allopeptides presented by allo-MHC or to a TCR misfocus on polymorphic amino acids on the α-helices of allo-MHC peptide-binding grooves (MHC-centric) [37,38,39]
Summary
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. Many alloreactive T cells display a degree of specificity reflective of traditional syngeneic T cells [2], a counterintuitive finding, given the prevailing theories that alloreactivity is driven by TCR “misfocusing” on non–self-MHC polymorphisms (MHC-centric) or the recognition of a repertoire of unique allopeptides (peptide-centric) [3]. This enigma has not been fully explained, it has led to a growing interest in the use of such “allospecific” TCRs in immunotherapy. Our results have broad implications for the determinants of immune recognition and efforts in immunotherapy
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call