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

Wang, Yuan; Singh, Nishant K.; Spear, Timothy T.; Hellman, Lance M.; Piepenbrink, Kurt H.; McMahan, Rachel H.; Rosen, Hugo R.; Vander Kooi, Craig W.; Nishimura, Michael I.; Baker, Brian M.

doi:10.1073/pnas.1700459114

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

Journal Article · Thu Jun 01 00:00:00 EDT 2017 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1700459114· OSTI ID:1437463

Wang, Yuan ^[1]; Singh, Nishant K. ^[1]; Spear, Timothy T. ^[2]; Hellman, Lance M. ^[1]; Piepenbrink, Kurt H. ^[3]; McMahan, Rachel H. ^[4]; Rosen, Hugo R. ^[4]; Vander Kooi, Craig W. ^[5]; Nishimura, Michael I. ^[2]; Baker, Brian M. ^[1]

Univ. of Notre Dame, IN (United States). Dept. of Chemistry and Biochemistry; Univ. of Notre Dame, IN (United States). Harper Cancer Research Institute
Loyola Univ. Chicago, Maywood, IL (United States). Dept. of Surgery and Cardinal Bernardin Cancer Center
Univ. of Nebraska, Lincoln, NE (United States)
Univ. of Colorado, Aurora, CO (United States). School of Medicine, Division of Gastroenterology & Hepatology
Univ. of Kentucky, Lexington, KY (United States)

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. Our research shows 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: National Institutes of Health (NIH)

Grant/Contract Number:: GM118166; CA154778; CA153789; CA180731

OSTI ID:: 1437463

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, Issue 24; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 33 works

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59 BASIC BIOLOGICAL SCIENCES
37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
T-cell receptor
peptide-MHC
structure
alloreactivity
specificity

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

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