Identification of a hepatitis C virus–reactive T cell receptor that does not require CD8 for target cell recognition

Callender, Glenda G.; Rosen, Hugo R.; Roszkowski, J; Lyons, Gretchen E.; Li, Mingli; Moore, Tamson V.; Brasic, Natasha; McKee, Mark D.; Nishimura, Michael I.

doi:10.1002/hep.21157

Cited by 36 publications

(52 citation statements)

References 30 publications

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“…1 A and B), with no recognition of nonpeptidepulsed targets or targets pulsed with the irrelevant tyrosinase:368-376 peptide (sequence YMDGTMSQV). As found previously (19,20,22), the TCR specifically recognized NS3/A2 in a CD8-independent manner. Modifications to the peptide had various effects, with alanine substitutions at p1 (Lys) and p6 (Gly) proving the most disruptive.…”

Section: Resultssupporting

confidence: 84%

“…Generation of CD8 + Jurkat cells has been described previously (19,47). Briefly, a modified SAMEN retroviral vector containing full-length human CD8 α and β, separated by an internal SRα promoter, and an internal ribosome entry site/neo r cassette was used to transduce cells.…”

Section: Discussionmentioning

confidence: 99%

“…HLA-A2 and A3/A30 belong to different class I MHC supertypes (17,18), and A2 has surface properties distinct from HLA-B, HLA-C, nonclassical class I, and the class II proteins. Expression of HCV1406 confers anti-HCV reactivity onto other effector cells, which specifically recognize NS3/HLA-A2 targets independent of the CD8 coreceptor and do not recognize irrelevant targets presented by A2 or other class I MHC proteins (19)(20)(21)(22).…”

Section: Significancementioning

confidence: 99%

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

Wang

Singh

Spear

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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

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Section: Resultssupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

See 1 more Smart Citation

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

Wang

Singh

Spear

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…However, not all patients develop this T cell response, and issues with HCV-specific T cells that are dysfunctional and incapable of secreting IFN-g effector cytokines upon HCV Ag stimulation have also been described (41), which differ from the TCR-redirected T cells shown in this study. It is true that a single response will not be able to mediate viral clearance, but as the research in this field is advancing, more HCV TCRs recognizing other viral targets can be identified with this approach, which could potentially be combined with the different HCV TCRs that have been identified so far (24,42,43). Reconstituting a multispecific antiviral T cell response would thus not be impossible in the near future and is worth consideration as an option for patients who are difficult to treat with antiviral drugs.…”

Section: Discussionmentioning

confidence: 99%

TCR-Redirected Human T Cells Inhibit Hepatitis C Virus Replication: Hepatotoxic Potential Is Linked to Antigen Specificity and Functional Avidity

Pasetto

Frelin

Aleman

et al. 2012

The Journal of Immunology

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Virus-specific CTL with high levels of functional avidity have been associated with viral clearance in hepatitis C virus (HCV) infection and with enhanced protective immunity. In chronic HCV infection, lack of antiviral CTL is frequently observed. In this study, we aim to investigate novel HCV TCRs that differ in Ag specificity. This involved isolating new HCV-specific murine TCRs that recognize a conserved HLA-A2–restricted CTL epitope within the nonstructural protein (NS) 5A viral protein and comparing them with TCRs recognizing another conserved CTL target in the NS3 viral protein. This was done by expressing the TCRs in human T cells and analyzing the function of the resulting TCR-transduced T cells. Our result indicates that these TCRs are efficiently assembled in transduced human T cells. They recognize peptide-loaded targets and demonstrate polyfunctional features such as IL-2, IFN-γ, and TNF-α secretion. However, in contrast to NS3-specific TCRs, the NS5A TCR-transduced T cells consist of a smaller proportion of polyfunctional T cells and require more peptide ligands to trigger the effector functions, including degranulation. Despite the differences, NS5A TCRs show effective inhibition of HCV replication in human hepatoma cells with persistent HCV RNA replication. Moreover, cellular injury demonstrated by aspartate aminotransferase release and cell death is less significant in the hepatoma cells following coincubation with NS5A TCR-transduced T cells, which is a property consistent with noncytotoxic antiviral CTLs. Our results suggest that HCV TCR-transduced T cells may be promising for the treatment of patients with chronic HCV infections.

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“…T cell lines that are specific to HLA-A2-restricted immunodominant CTL epitopes within the HCV NS3 and NS5A viral proteins (Callender et al 2006;Pasetto et al 2012a, b;Zhang et al 2010). The retroviral-mediated vector technology was utilized to transfer new TCRs (isolated from HCV patients or HCV vaccinated HLA-transgenic mice) to healthy T cells from blood donors, as well as from HCVinfected individuals.…”

Section: Transfer Of Exogenous T Cell Receptormentioning

confidence: 99%

Functional Attributes of Responding T Cells in HCV Infection: The Recent Advances in Engineering Functional Antiviral T Cells

Pasetto

Aleman

Chen

2013

Arch. Immunol. Ther. Exp.

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Hepatitis C virus (HCV) is one of the major causes of hepatocellular carcinoma (HCC) around the world. HCV promotes characteristics of cancer stem cells and the infected cells are insensitive to apoptotic signals, which lead to persistent antigen stimulation and T cell exhaustion in the host. In spite of new effective antiviral drugs, new challenges are around the corner as drugresistant viral strains and drug-drug interactions have already been reported. Considering that there are few effective treatments available for HCC, novel immunotherapies to prevent HCC and late stage HCV-related liver diseases should be considered. Given that adoptive immunotherapy with antigen-specific T lymphocytes has emerged as an effective therapeutic strategy for combating cancer, there is, therefore, reason to examine the possibility of using highly functional HCV-reactive T cells in immunotherapy. This review aims to provide the current understanding of natural HCV responding T cells in HCV infection and to give an update on the novel approaches that have the capacity to ex vivo generate functional T cells for potential adoptive cell therapy. Approaches based on the pMHC tetramer-associated magnetic enrichment, exogenous HCV T cell receptor transfer, and induced pluripotent stem cell technologies are described herein. Their potentials as immunotherapeutic against HCV-related diseases are discussed.

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Identification of a hepatitis C virus–reactive T cell receptor that does not require CD8 for target cell recognition

Cited by 36 publications

References 30 publications

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

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

TCR-Redirected Human T Cells Inhibit Hepatitis C Virus Replication: Hepatotoxic Potential Is Linked to Antigen Specificity and Functional Avidity

Functional Attributes of Responding T Cells in HCV Infection: The Recent Advances in Engineering Functional Antiviral T Cells

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