Structural basis for the recognition of mutant self by a tumor-specific, MHC class II–restricted T cell receptor

Deng, Lu; Langley, Ries J.; Brown, Patrick H.; Xu, Gang; Teng, Leslie; Wang, Qian; Gonzales, Mónica; Callender, Glenda G.; Nishimura, Michael I.; Topalian, Suzanne L.; Mariuzza, Roy A.

doi:10.1038/ni1447

Cited by 94 publications

(124 citation statements)

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“…1A12 the CDR3 loops converge on residue P2 (Figure 3c,d). Consistent with the idea that the N-terminal portion of peptides is intrinsically unfavorable for TCR binding [10], E8 resembles autoimmune TCR in binding TPI-DR1 (wild-type or mutant peptide) with low affinity, although affinity is increased by the Thr-to-Ile mutation at TCR-contacting position P3 of TPI [12].Also in common with autoimmune TCR 3A6 and Ob.1A12, the CDR3 loops of E8 form a broad pocket that accommodates two ligand residues (P3 and P5) (Figure 3b,f), whereas the corresponding, but narrower, pocket of anti-foreign TCR generally contains only a single residue (P5). As for anti-foreign complexes, the E8-mutTPI-DR1 structure indicates that residue P5 is crucial for TCR recognition, whereas the P5 position is relatively tolerant of substitutions in the 3A6-MBP-DR2a and Ob.1A12-MBP-DR2b complexes, in which P5 lies outside the CDR3 pocket (Figure 3c,d).…”

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confidence: 56%

“…The structure of a human tumor-specific TCR (E8) bound to mutTPI and HLA-DR1 has provided information on T-cell recognition of a naturally mutated self-antigen compared with recognition of native self or foreign antigens [12]. The E8-mutTPI-DR1 complex revealed several features intermediate between those of anti-foreign and autoimmune TCR-peptide-MHC class II complexes that might reflect the hybrid nature of altered self.…”

Section: Recognition Of Altered Self By a Human Melanoma-specific Tcrmentioning

confidence: 99%

“…An example of the former mechanism is a unique HLA-DR1-restricted human melanoma antigen derived from the glycolytic enzyme triosephosphate isomerase (TPI), in which a naturally occurring point mutation replaced a threonine residue with isoleucine within the recognized epitope [47]. Presentation of wild-type and mutant TPI (mutTPI) peptides to melanoma-specific CD4 + tumor-infiltrating lymphocytes by HLA-DR1 results in dramatically different T-cell responses, such that recognition is enhanced 100 000-fold for the mutant relative to the wild-type peptide.The structure of a human tumor-specific TCR (E8) bound to mutTPI and HLA-DR1 has provided information on T-cell recognition of a naturally mutated self-antigen compared with recognition of native self or foreign antigens [12]. The E8-mutTPI-DR1 complex revealed several features intermediate between those of anti-foreign and autoimmune TCR-peptide-MHC class II complexes that might reflect the hybrid nature of altered self.…”

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confidence: 99%

“…It is also noteworthy that low affinity for self-peptide-MHC does not necessarily preclude T-cell activation by low concentrations of the self-ligand. Various models have been proposed to explain this phenomenon, including peptide-driven formation of TCR dimers for enhancing T-cell sensitivity [12,[48][49][50]. However, the actual existence of such signaling intermediates on the T-cell surface remains to be established.…”

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confidence: 99%

“…Here we review structural studies of self-recognition by autoimmune TCR [8][9][10][11], and of altered self-recognition by tumor-specific TCR [12]. We focus on MHC class II-restricted TCR because susceptibility to autoimmune diseases is more strongly linked to MHC class II than class I.…”

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confidence: 99%

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Recognition of self-peptide–MHC complexes by autoimmune T-cell receptors

Deng

Mariuzza

2007

Trends in Biochemical Sciences

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T cell receptors (TCR) recognize antigenic peptides displayed by MHC molecules. Whereas T-cell recognition of foreign peptides is essential for immune defense against microbial pathogens, recognition of self-peptides can cause autoimmune disease. Structural studies of anti-foreign TCR showed remarkable similarities in the topology of TCR binding to peptide-MHC, which maximize interactions with the ligand. However, recent structures involving autoimmune and tumor-specific TCR have revealed that they engage self-peptide-MHC with different topologies, which are suboptimal for TCR binding. These differences might reflect the distinct selection pressures exerted on anti-microbial versus autoreactive T cells. The structures also provide new insights into TCR cross-reactivity, which can contribute to autoimmunity by increasing the likelihood of self-peptide-MHC recognition. T-cell recognition of non-self, self and mutant selfThe immune system has evolved in response to the need for distinguishing non-self pathogens from self tissues. Discrimination is mediated by T-cell receptors (TCR), which recognize peptide fragments (epitopes) bound to MHC molecules on the surface of antigen-presenting cells (APC) (Box 1). These peptides are generated by proteolytic degradation of self or foreign proteins within cells expressing MHC class I or II molecules in a process known as antigen presentation [1]. Whereas T-cell recognition of foreign peptides is vital for defense against invading microorganisms, recognition of self-peptides can lead to autoimmune disease. A third category of T-cell epitopes involves self-peptides resulting from mutations accumulated during aging or disease [2,3]. However, in terms of T-cell recognition, the boundaries separating foreign, self, and altered-self epitopes are not necessarily absolute. For example, immunity to cancer can arise from mutations in self-proteins, which render them visible to T cells [2,3], a process that might also induce autoimmunity [4]. Similarly, autoimmunity can be triggered by viral or bacterial peptides that mimic self-peptides [5,6].Although much is known about TCR recognition of foreign antigens [7], the structural and biophysical principles governing TCR recognition of self and mutant-self have only recentlyCorresponding author: Mariuzza, R.A. (mariuzza@carb.nist.gov). Publisher's Disclaimer: This article was published in an Elsevier journal. The attached copy is furnished to the author for non-commercial research and education use, including for instruction at the author's institution, sharing with colleagues and providing to institution administration. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. Sources of autoimmunityThe ability to distinguish between self and non-self is known as immunological tolerance, and involves the removal of autoreactive T cells by negative s...

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confidence: 56%

Section: Recognition Of Altered Self By a Human Melanoma-specific Tcrmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Recognition of self-peptide–MHC complexes by autoimmune T-cell receptors

Deng

Mariuzza

2007

Trends in Biochemical Sciences

Self Cite

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Characterizing Protein‐Protein Interactions by Sedimentation Velocity Analytical Ultracentrifugation

2008

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This unit introduces the basic principles and practice of sedimentation velocity analytical ultracentrifugation for the study of reversible protein interactions, such as the characterization of self-association, heterogeneous association, multi-protein complexes, binding stoichiometry, and the determination of association constants. The analytical tools described include sedimentation coefficient and molar mass distributions, multi-signal sedimentation coefficient distributions, Gilbert-Jenkins theory, different forms of isotherms, and global Lamm equation modeling. Concepts for the experimental design are discussed, and a detailed step-by-step protocol guiding the reader through the experiment and the data analysis is available as an Internet resource.

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Survey of the year 2007 commercial optical biosensor literature

Rich

Myszka

2008

J of Molecular Recognition

166

121

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In 2007, 1179 papers were published that involved the application of optical biosensors. Reported developments in instrument hardware, assay design, and immobilization chemistry continue to improve the technology's throughput, sensitivity, and utility. Compared to recent years, the widest range of platforms, both traditional format and array-based, were used. However, as in the past, we found a disappointingly low percentage of well-executed experiments and thoughtful data interpretation. We are alarmed by the high frequency of suboptimal data and over-interpreted results in the literature. Fortunately, learning to visually recognize good--and more importantly, bad--data is easy. Using examples from the literature, we outline several features of biosensor responses that indicate experimental artifacts versus actual binding events. Our goal is to have everyone, from benchtop scientists to project managers and manuscript reviewers, become astute judges of biosensor results using nothing more than their eyes.

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Structural basis for the recognition of mutant self by a tumor-specific, MHC class II–restricted T cell receptor

Cited by 94 publications

References 53 publications

Recognition of self-peptide–MHC complexes by autoimmune T-cell receptors

Recognition of self-peptide–MHC complexes by autoimmune T-cell receptors

Characterizing Protein‐Protein Interactions by Sedimentation Velocity Analytical Ultracentrifugation

Survey of the year 2007 commercial optical biosensor literature

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