The Crystal Structure of a T Cell Receptor in Complex with Peptide and MHC Class II

Reinherz, Ellis L.; Tan, Kemin; Tang, Lei; Kern, Petra; Liu, Jin-huan; Xiong, Yongqiang; Hussey, Rebecca E.; Smolyar, Alex; Hare, Brian; Zhang, Rongguang; Joachimiak, Andrzej; Chang, Huiyou; Wagner, Gerhard; Wang, Jia-Huai

doi:10.1126/science.286.5446.1913

Cited by 371 publications

(330 citation statements)

References 123 publications

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“…This peptide has been identified as a relevant MHC class I (K b ) epitope (43,44), but Wang et al (31) have reported that immunization with DCs loaded with TRP-2 180 -188 peptide fused to a cell-penetrating peptide induce a CD4 ϩ T cell response as well, and that this is required for antitumor immunity, as evidenced by CD4 ϩ T cell depletion and the use of CD4 ϩ knockout mice. Peptides are known to bind to MHC class II molecules via a nine amino acid core sequence (57)(58)(59), and this 9-aa core also is recognized by the TCR (60). Therefore, the strong CD4 T cell response to TRP-2 that we observed is not totally surprising.…”

Section: Discussionsupporting

confidence: 49%

Dendritic Cells Charged with Apoptotic Tumor Cells Induce Long-Lived Protective CD4+ and CD8+ T Cell Immunity against B16 Melanoma

Goldszmid

Idoyaga

Bravo³

et al. 2003

The Journal of Immunology

177

143

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Dendritic cells (DCs) are potent APCs and attractive vectors for cancer immunotherapy. Using the B16 melanoma, a poorly immunogenic experimental tumor that expresses low levels of MHC class I products, we investigated whether DCs loaded ex vivo with apoptotic tumor cells could elicit combined CD4+ and CD8+ T cell dependent, long term immunity following injection into mice. The bone marrow-derived DCs underwent maturation during overnight coculture with apoptotic melanoma cells. Following injection, DCs migrated to the draining lymph nodes comparably to control DCs at a level corresponding to ∼0.5% of the injected inoculum. Mice vaccinated with tumor-loaded DCs were protected against an intracutaneous challenge with B16, with 80% of the mice remaining tumor-free 12 wk after challenge. CD4+ and CD8+ T cells were efficiently primed in vaccinated animals, as evidenced by IFN-γ secretion after in vitro stimulation with DCs loaded with apoptotic B16 or DCs pulsed with the naturally expressed melanoma Ag, tyrosinase-related protein 2. In addition, B16 melanoma cells were recognized by immune CD8+ T cells in vitro, and cytolytic activity against tyrosinase-related protein 2180–188-pulsed target cells was observed in vivo. When either CD4+ or CD8+ T cells were depleted at the time of challenge, the protection was completely abrogated. Mice receiving a tumor challenge 10 wk after vaccination were also protected, consistent with the induction of tumor-specific memory. Therefore, DCs loaded with cells undergoing apoptotic death can prime melanoma-specific helper and CTLs and provide long term protection against a poorly immunogenic tumor in mice.

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Section: Discussionsupporting

confidence: 49%

Dendritic Cells Charged with Apoptotic Tumor Cells Induce Long-Lived Protective CD4+ and CD8+ T Cell Immunity against B16 Melanoma

Goldszmid

Idoyaga

Bravo³

et al. 2003

The Journal of Immunology

177

143

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“…Recently, the crystal structure of the CA 134 -146 /I-A k complex has been solved and the I-A k anchor residues identified in this structure support our model of RNase/I-A k (21). In this structure, there is a non-D, H, at P1, a small hydrophobic A at P4, the same E at P6, and a small residue G at P9.…”

Section: Four Amino Acids Of Rn 42-56 Bound To I-a K Can Contact a Tcrsupporting

confidence: 50%

Molecular Basis for Recognition of an Arthritic Peptide and a Foreign Epitope on Distinct MHC Molecules by a Single TCR

Basu

Horváth

Matsumoto

et al. 2000

The Journal of Immunology

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KRN TCR transgenic T cells recognize two self-MHC molecules: a foreign peptide, bovine RNase 42–56, on I-Ak and an autoantigen, glucose-6-phosphate isomerase 282–294, on I-Ag7. Because the latter recognition event initiates a disease closely resembling human rheumatoid arthritis, we investigated the structural basis of this pathogenic TCR’s dual specificity. While peptide recognition is altered to a minor degree between the MHC molecules, we show that the receptor’s cross-reactivity critically depends upon a TCR contact residue completely conserved in the foreign and self peptides. Further, the altered recognition of peptide derives from discrete differences on the MHC recognition surfaces and not the disparate binding grooves. This work provides a detailed structural comparison of an autoreactive TCR’s interactions with naturally occurring peptides on distinct MHC molecules. The capacity to interact with multiple self-MHCs in this manner increases the number of potentially pathogenic self-interactions available to a T cell.

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“…The structure of the 3K peptide bound to IA b reveals five upwardly pointing amino acids as potential candidates for recognition by the ␣␤ T cell antigen receptors (TCR): the p-1Glu, p2Gln, p3Lys, p5Lys, and p8Lys. The side chains of these amino acids are at least partially exposed on the molecule surface and fall within the footprints seen of the ␣␤TCRs on other MHCII͞peptide complexes (51,52). To test whether these are indeed important for recognition, we synthesized a set of mutant peptides in which each of these amino acids was mutated to Ala.…”

Section: Resultsmentioning

confidence: 99%

Alternate interactions define the binding of peptides to the MHC molecule IA^b

Liu

Dai

Crawford

et al. 2002

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

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T he crystal structures of a variety of MHCI (1-9) and MHCII (10-23) molecules have revealed their features that lead to stable peptide binding. Conserved amino acids of MHCI interact with the N terminus and C terminus of the peptide in virtually all isotypes and alleles. Between these termini, the peptide can vary in length and in the path it takes through the binding groove, often bulging out of the groove in the middle. In MHCII, the N and C termini of the peptide generally extend beyond the binding groove and do not interact with the MHCII molecule. Rather, H-bonding interactions between the peptide backbone and conserved amino acids of the MHCII ␣-helices force the peptide to take a similar, extended path through the groove of all MHCII isotypes and alleles.The unique interactions that determine the allelic specificity of peptide binding seem to be controlled by the character of pockets within the interior of the binding groove that preferentially accept particular amino acid side chains. Because the MHC amino acids that line these pockets are among the most genetically variable, their depth, shape, and chemistry vary considerably among MHC alleles and isotypes, and they appear to be the most important factor in the specificity of peptide binding.In the current study we have solved the crystal structure of the mouse MHCII molecule IA b with a bound immunogenic peptide variant of a dominant peptide derived from the MHCII E␣ protein that is found in IA b in some strains of mice (24). Despite the high stability and immunogenicity of this complex, the four usual p1, p4, p6, and p9 peptide side chain binding pockets of IA b are largely unfilled, because alanines occur in the peptide at these positions. Rather, the stability of this peptide͞MHCII complex can be attributed to the combination of the conserved interactions with the peptide backbone as well as extensive unique interactions of the IA b molecule with other peptide amino acids particularly at the N-terminal end and the p7 position of the peptide. These results suggest that IA b can achieve stable peptide binding in more than one way and may account for the previous difficulty in defining the IA b peptidebinding motif. Materials and MethodsPreparation of Soluble IA b . The production of soluble IA b containing a peptide attached to the ␤-chain N terminus via a flexible peptide linker has been described (25). In the original constructions, peptides included both the E␣-derived peptide, ASFEAQGALANIAVDKA (pE␣), which occupies about 10% of natural IA b , and an immunogenic variant, ASFEAQKAK-ANKAVDKA (p3K), in which three positions in the peptide (underlined) had lysines substituted for the E␣ peptide amino acids. For crystallization, the construct was altered to use a shortened form of p3K, FEAKGAKANKAVD, and to shorten the IA b ␣ and ␤ chains to the predicted ends of the ␣2 and ␤2 domains. The construct was cloned into a previously described dual promoter baculovirus transfer vector (26, 27) and introduced into BacVector 3000 version of AcNPV baculovirus ...

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The Crystal Structure of a T Cell Receptor in Complex with Peptide and MHC Class II

Cited by 371 publications

References 123 publications

Dendritic Cells Charged with Apoptotic Tumor Cells Induce Long-Lived Protective CD4+ and CD8+ T Cell Immunity against B16 Melanoma

Dendritic Cells Charged with Apoptotic Tumor Cells Induce Long-Lived Protective CD4+ and CD8+ T Cell Immunity against B16 Melanoma

Molecular Basis for Recognition of an Arthritic Peptide and a Foreign Epitope on Distinct MHC Molecules by a Single TCR

Alternate interactions define the binding of peptides to the MHC molecule IA^b

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The Crystal Structure of a T Cell Receptor in Complex with Peptide and MHC Class II

Cited by 371 publications

References 123 publications

Dendritic Cells Charged with Apoptotic Tumor Cells Induce Long-Lived Protective CD4+ and CD8+ T Cell Immunity against B16 Melanoma

Dendritic Cells Charged with Apoptotic Tumor Cells Induce Long-Lived Protective CD4+ and CD8+ T Cell Immunity against B16 Melanoma

Molecular Basis for Recognition of an Arthritic Peptide and a Foreign Epitope on Distinct MHC Molecules by a Single TCR

Alternate interactions define the binding of peptides to the MHC molecule IAb

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Alternate interactions define the binding of peptides to the MHC molecule IA^b