T-cell allorecognition: a case of mistaken identity or déjà vu?

Archbold, J.K.; Macdonald, W.A.; Burrows, Scott R.; Rossjohn, Jamie; McCluskey, James

doi:10.1016/j.it.2008.02.005

Cited by 45 publications

(53 citation statements)

References 68 publications

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“…The surprising specificity of many alloreactive TCRs and structural studies of alloreactive complexes have challenged these theories (3,12,13). Highly specific alloreactive T cells and TCRs are being explored for targeting what otherwise would be poorly immunogenic shared tumor antigens and have been adopted for treatment of posttransplantationassociated lymphoproliferative disease (4,6,7).…”

Section: Discussionmentioning

confidence: 99%

“…An overall assessment of these structures is that rather than demonstrating features that are clearly characteristic of alloreactivity, they illustrate features similar to traditional syngeneic complexes of TCRs with peptides presented by self-MHC (3,12,13). The LC13 TCR, for example, was recently shown to engage allo-and self-MHC almost identically, and could distinguish between closely related class I alleles (14,15).…”

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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: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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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“…To achieve this ambitious goal, it is crucial to understand the molecular target structures recognized by alloreactive donor T cells mediating these effects. 9,10 These target structures are fundamentally different in allo-HCT from HLA-matched sibling and unrelated donors (UDs), which are often erroneously considered as a single entity ("HLA-matched" HCT). However, in sibling HCT the targets of T-cell alloreactivity are almost exclusively minor histocompatibility antigens (mHAgs), [11][12][13] whereas most HLAmatched UDs additionally present mismatches for the HLA-DP antigens encoded in the major histocompatibility complex (MHC).…”

Section: Introductionmentioning

confidence: 99%

“…30 Of note, genetic disparity between unrelated individuals frequently includes the HLA-DRB3/4/5, -DQ, and -DP loci which are targets of direct T-cell alloreactivity, that is, cross-recognition by T cells specific for different self-HLA-restricted peptides regardless of their derivation from novel or recall antigens. 9,10,31 This phenomenon explains why T cells mediating direct alloreactivity are found both in the naive and memory repertoire and have a surprisingly high precursor frequency of at least 1%. 10,24,26,32 HLA-DRB3/4/5, -DQ, and -DP have relatively …”

Section: Introductionmentioning

confidence: 99%

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HLA-DP in unrelated hematopoietic cell transplantation revisited: challenges and opportunities

Fleischhauer

Shaw

2017

Blood

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When considering HLA-matched hematopoietic cell transplantation (HCT), sibling and unrelated donors (UDs) are biologically different because UD-HCT is typically performed across HLA-DP disparities absent in sibling HCT. Mismatched HLA-DP is targeted by direct alloreactive T cell responses with important implications for graft-versus-host disease and graft-versus-leukemia. This concise review details special features of HLA-DP as model antigens for clinically permissive mismatches mediating limited T-cell alloreactivity with minimal toxicity, and describes future avenues for their exploitation in cellular immunotherapy of malignant blood disorders.

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Selection of T‐cell receptors with a recurrent CDR3β peptide‐contact motif within the repertoire of alloreactive CD8⁺ T cells

et al. 2011

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Peptide/MHC complexes recognized by alloreactive T lymphocytes (TLs) have been identified, but their contribution to in vivo allo-rejection is not known. We previously characterized the peptide pBM1, highly represented among endogenous H-2K ing that it is recruited upon immunization for its optimal TCR-peptide/MHC fit. Thus, a CDR3b motif generated by a process akin to ''convergent recombination'' accounts for a sizable fraction of the alloreactive anti-K b TCR repertoire.

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T-cell allorecognition: a case of mistaken identity or déjà vu?

Cited by 45 publications

References 68 publications

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

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

HLA-DP in unrelated hematopoietic cell transplantation revisited: challenges and opportunities

Selection of T‐cell receptors with a recurrent CDR3β peptide‐contact motif within the repertoire of alloreactive CD8⁺ T cells

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T-cell allorecognition: a case of mistaken identity or déjà vu?

Cited by 45 publications

References 68 publications

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

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

HLA-DP in unrelated hematopoietic cell transplantation revisited: challenges and opportunities

Selection of T‐cell receptors with a recurrent CDR3β peptide‐contact motif within the repertoire of alloreactive CD8+ T cells

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Product

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Selection of T‐cell receptors with a recurrent CDR3β peptide‐contact motif within the repertoire of alloreactive CD8⁺ T cells