T Cells Can Be Activated by Peptides That Are Unrelated in Sequence to Their Selecting Peptide

Ignatowicz, Leszek; Rees, William; Pacholczyk, Rafał; Ignatowicz, Hanna; Kushnir, E; Kappler, John W.; Marrack, Philippa

doi:10.1016/s1074-7613(00)80521-x

Cited by 113 publications

(95 citation statements)

References 36 publications

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“…In this version of the peptide (p3K), three positions in pE␣ were changed to Lys residues. We have shown previously that this peptide binds to IA b as stably as pE␣ does (39) and is very immunogenic in IA b -expressing mice (25,39).…”

Section: Resultsmentioning

confidence: 90%

“…Our previous studies have shown that p3K binds very strongly to IA b and, when bound to soluble IA b , forms a very stable molecule (25,39). How is this stability maintained in the face of virtually no occupancy of the conventional side chain binding pockets?…”

Section: Resultsmentioning

confidence: 99%

“…There are many studies of peptides bound to IA b (39,40,47,48). However, these studies alone have not yet yielded a consensus on the peptide binding motif for IA b .…”

Section: Resultsmentioning

confidence: 99%

“…For example, the alignment of the DO-11.10 reactive ovalbumin peptide described above that places amino acids with small side chains in the p1, p4, p6, and p9 pockets also puts a favorable Asn at p7. Another variant of pE␣ that is immunogenic in IA b -expressing mice and binds very well to IA b has Trp substituted at positions p2 and p8 (25,39), but otherwise has the same potential interactions with IA b as p3K and pE␣.…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 90%

Section: Resultsmentioning

confidence: 99%

“…There are many studies of peptides bound to IA b (39,40,47,48). However, these studies alone have not yet yielded a consensus on the peptide binding motif for IA b .…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

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.

Self Cite

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“…27 Furthermore, these CD4 1 T cells reacted with the same MHC class II molecule bound to other antigenic peptides, including one that was quite different from the selecting peptide in TCR-binding residues. 28 Thus, the TCR crossreactivity is not an unusual phenomenon and may represent an important aspect of TCR recognition in the thymus as well as in the periphery. 23,29,30 However, the presence of the TCR crossreactivity also constitutes the structural basis for heterologous immunity in which a particular T-cell response to a given antigen may influence their responses to other unrelated antigens.…”

Section: Specificity and Plasticity Of Tcrsmentioning

confidence: 99%

Cross-immune tolerance: conception and its potential significance on transplantation tolerance

Zhao

2009

Cell Mol Immunol

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The myelin basic protein-specific T cell repertoire in Lewis rats: T cell receptor diversity is influenced both by intrathymic milieu and by extrathymic peptide presentation

et al. 1998

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In the Lewis rat, the T lymphocyte response to guinea pig myelin basic protein (MBP) is focused almost exclusively on epitopes nested in the MBP peptide sequence p68-88, and is dominated by T cell receptors (TCR) using Vbeta8.2 gene elements, together with short N(D)N regions. Here we analyzed MBP-specific TCR from Lewis T cells differentiating in chimeric thymuses of Lewis rat/SCID mouse chimeras, in the absence of an intact rat thymic microenvironment (SCID(FL) mice). In these T cells, the TCR Vbeta repertoire is broad, N(D)N regions are significantly longer, and contain regular rates of template-independent N nucleotides. In striking contrast, a Vbeta8.2 biased TCR repertoire and few N-region inserts are seen in p68-88-specific, Lewis rat-derived T cells differentiating in the complete rat thymic microenvironment provided by chimeric SCID mice bearing embryonic Lewis thymus grafts (SCID(FL/FT) mice). A T cell repertoire resembling the one in SCID(FL) mice is used by T cells of intact Lewis rats following immunization with a truncated epitope of MBP, p69-86. Also this selection generates a broad TCR Vbeta pattern with long N(D)N regions, and higher numbers of N nucleotides. These results show that both intrathymic repertoire selection, and extrathymic peptide priming exert profound effects on the TCR usage in the anti-MBP response of Lewis rats.

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T Cells Can Be Activated by Peptides That Are Unrelated in Sequence to Their Selecting Peptide

Cited by 113 publications

References 36 publications

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

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

Cross-immune tolerance: conception and its potential significance on transplantation tolerance

The myelin basic protein-specific T cell repertoire in Lewis rats: T cell receptor diversity is influenced both by intrathymic milieu and by extrathymic peptide presentation

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T Cells Can Be Activated by Peptides That Are Unrelated in Sequence to Their Selecting Peptide

Cited by 113 publications

References 36 publications

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

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

Cross-immune tolerance: conception and its potential significance on transplantation tolerance

The myelin basic protein-specific T cell repertoire in Lewis rats: T cell receptor diversity is influenced both by intrathymic milieu and by extrathymic peptide presentation

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

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