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

Authors: Wang, Y.; Singh, N. K.; Spear, T. T.; Hellman, L. M.; Piepenbrink, K. H.; McMahan, R. H.; Rosen, H. R.; Vander Kooi, C. W.; Nishimura, M. I.; Baker, B. M.
Article Title: 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 quot;hot spotquot; 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.
Keywords: Surgery; T-cell receptor; structure; peptide-MHC; specificity; alloreactivity
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 114
Issue: 24
ISSN: 1091-6490; 0027-8424
Publisher: Unknown  
Journal Place: United States
Date Published: 2017
Start Page: E4792
End Page: E4801
Language: eng
Notes: LR: 20170614; PDB/5JZI; JID: 7505876; OTO: NOTNLM; ppublish