The structure of the human allo‐ligand HLA‐B*3501 in complex with a cytochrome p450 peptide: Steric hindrance influences TCR allo‐recognition

Hourigan, Christopher S.; Harkiolaki, Maria; Peterson, Neil A.; Bell, John I.; Jones, E Y; O’Callaghan, Christopher A.

doi:10.1002/eji.200636234

Cited by 10 publications

(9 citation statements)

References 29 publications

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“…There was no secondary anchor residue in any of the HLA-B*3501-NP 418 structures. This is in contrast to other peptide-HLA-B*3501 structures solved to date, which typically use P5-D or P5-L as the secondary anchor residues (17)(18)(19) (Fig. 4) bulges out of the binding cleft, exposing its side chain to the solvent for potential contact by the TCR.…”

Section: Resultsmentioning

confidence: 73%

Cross-reactive CD8 ⁺ T-cell immunity between the pandemic H1N1-2009 and H1N1-1918 influenza A viruses

Gras

Kędzierski

Valkenburg

et al. 2010

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

173

169

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Preexisting T-cell immunity directed at conserved viral regions promotes enhanced recovery from influenza virus infections, with there being some evidence of cross-protection directed at variable peptides. Strikingly, many of the immunogenic peptides derived from the current pandemic A(H1N1)-2009 influenza virus are representative of the catastrophic 1918 “Spanish flu” rather than more recent “seasonal” strains. We present immunological and structural analyses of cross-reactive CD8 + T-cell–mediated immunity directed at a variable (although highly cross-reactive) immunodominant NP 418–426 peptide that binds to a large B7 family (HLA-B*3501/03/0702) found throughout human populations. Memory CD8 + T-cell specificity was probed for 12 different NP 418 mutants that emerged over the 9 decades between the 1918 and 2009 pandemics. Although there is evidence of substantial cross-reactivity among seasonal NP 418 mutants, current memory T-cell profiles show no preexisting immunity to the 2009-NP 418 variant or the 1918-NP 418 variant. Natural infection with the A(H1N1)-2009 virus, however, elicits CD8 + T cells specific for the 2009-NP 418 and 1918-NP 418 epitopes. This analysis points to the potential importance of cross-reactive T-cell populations that cover the possible spectrum of T-cell variants and suggests that the identification of key residues/motifs that elicit cross-reactive T-cell sets could facilitate the evolution of immunization protocols that provide a measure of protection against unpredicted pandemic influenza viruses. Thus, it is worth exploring the potential of vaccines that incorporate peptide variants with a proven potential for broader immunogenicity, especially to those that are not recognized by the current memory T-cell pool generated by exposure to influenza variants that cause successive seasonal epidemics.

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Section: Resultsmentioning

confidence: 73%

Cross-reactive CD8 ⁺ T-cell immunity between the pandemic H1N1-2009 and H1N1-1918 influenza A viruses

Gras

Kędzierski

Valkenburg

et al. 2010

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

173

169

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“…Furthermore, the structure of B*3501 in complex with an octameric peptide reveals that the pentagonal network can also exist in a slightly modified form in which the N terminus of the peptide is shifted upwards, preventing its direct participation but permitting the establishment of a connection to the pentagonal network through a water molecule (53), instead of forming one of the five corners of the pentagonal network. The latter represents the "normal" situation and can be found in HLA-B35 molecules presenting nonameric peptides (15,16,59), in all other published structures of "classical" MHC class I molecules, or in the structures of the HLA-B27 subtypes with the pCatA peptide described here. A comparison of the binding of the nonameric Tax peptide (Tax9) and an N-terminally truncated octamer (Tax8) to HLA-A2 shows that the removal of p1, a residue essential for formation of the pentagonal network, significantly reduces the affinity of the interaction between the ligand and the A pocket (54), but it does not eliminate the pentagonal network that is present in the Tax9 as well as the Tax8 peptide structures, with positions of the p1 atoms crucial for connecting the peptide with the ring formed by water molecules in the Tax8 structure.…”

Section: Discussionmentioning

confidence: 99%

Structural Basis for T Cell Alloreactivity among Three HLA-B14 and HLA-B27 Antigens

Kumar

Vahedi-Faridi

Merino

et al. 2009

Journal of Biological Chemistry

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The existence of cytotoxic T cells (CTL) cross-reacting with the human major histocompatibility antigens HLA-B14 and HLA-B27 suggests that their alloreactivity could be due to presentation of shared peptides in similar binding modes by these molecules. We therefore determined the crystal structures of the subtypes HLA-B*1402, HLA-B*2705, and HLA-B*2709 in complex with a proven self-ligand, pCatA (peptide with the sequence IRAAPPPLF derived from cathepsin A (residues 2-10)), and of HLA-B*1402 in complex with a viral peptide, pLMP2 (RRRWRRLTV, derived from latent membrane protein 2 (residues 236 -244) of Epstein-Barr virus). Despite the exchange of 18 residues within the binding grooves of HLA-B*1402 and HLA-B*2705 or HLA-B*2709, the pCatA peptide is presented in nearly identical conformations. However, pLMP2 is displayed by HLA-B*1402 in a conformation distinct from those previously found in the two HLA-B27 subtypes. In addition, the complexes of HLA-B*1402 with the two peptides reveal a nonstandard, tetragonal mode of the peptide N terminus anchoring in the binding groove because of the exchange of the common Tyr-171 by His-171 of the HLA-B*1402 heavy chain. This exchange appears also responsible for reduced stability of HLA-B14-peptide complexes in vivo and slow assembly in vitro. The studies with the pCatA peptide uncover that CTL cross-reactive between HLA-B14 and HLA-B27 might primarily recognize the common structural features of the bound peptide, thus neglecting amino acid replacements within the rim of the binding grooves. In contrast, structural alterations between the three complexes with the pLMP2 peptide indicate how heavy chain polymorphisms can influence peptide display and prevent CTL cross-reactivity between HLA-B14 and HLA-B27 antigens.T cells possessing the ability to recognize major histocompatibility complex (MHC) 2 molecules from another individual of the same species, also termed alloreactive T cells, may constitute up to 10% of the T cell pool of an individual, and their precursor frequency can be 100 -1,000-fold higher than that of self-restricted T cells directed against a foreign peptide (1, 2). The ability of alloreactive T cells to cross-react with nonself-MHC molecules is a major obstacle preventing successful organ transplantations (3-5). Two mechanisms, direct or indirect allorecognition, can be responsible for the rejection of a transplant by alloreactive T cells (6). In the first case, donor cells expressing MHC molecules are directly recognized by host T cells (7), whereas indirect allorecognition involves the presentation of peptides derived from donor proteins by MHC molecules of the host, followed by the detection of the complexes by the host T cells (8). However, although alloreactive T cells are very common and of great clinical importance, neither the primary basis for their existence nor the reasons underlying their cross-reactivity are sufficiently understood to draw general conclusions (9 -11). Only very few studies have addressed the structural basis for the recognition...

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“…7,8,[13][14][15] In these studies, reactivity against target cells exogenously loaded with high concentrations of peptide was interpreted as biologic relevant reactivity, and recognition of different peptides presented in allo-MHC by alloreactive T cells was concluded to represent bona fide polyspecific allorecognition. However, because recognition of exogenously loaded peptides in the absence of reactivity against endogenously processed and presented Ag may represent low-avidity T-cell recognition, biologic relevance of reactivity against synthetic peptide-loaded target cells needs to be confirmed by investigating the T-cell reactivity against endogenously processed and presented Ag.…”

Section: Introductionmentioning

confidence: 99%

Allo-HLA–reactive T cells inducing graft-versus-host disease are single peptide specific

Amir

Steen

Hagedoorn

et al. 2011

Blood

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T-cell alloreactivity directed against nonself-HLA molecules has been assumed to be less peptide specific than conventional T-cell reactivity. A large variation in degree of peptide specificity has previously been reported, including single peptide specificity, polyspecificity, and peptide degeneracy. Peptide polyspecificity was illustrated using synthetic peptide-loaded target cells, but in the absence of confirmation against endogenously processed peptides this may represent low-avidity T-cell reactivity. Peptide degeneracy was concluded based on recognition of Ag-processing defective cells. In addition, because most investigated alloreactive T cells were in vitro activated and expanded, the previously determined specificities may have not been representative for alloreactivity in vivo. To study the biologically relevant peptide specificity and avidity of alloreactivity, we investigated the degree of peptide specificity of 50 different allo-HLA-reactive T-cell clones which were activated and expanded in vivo during GVHD. All but one of the alloreactive T-cell clones, including those reactive against Ag-processing defective T2 cells, recognized a single peptide allo-HLA complex, unique for each clone. Downregulation of the expression of the recognized Ags using silencing shRNAs confirmed single peptide specificity. Based on these results, we conclude that biologically relevant alloreactivity selected during in vivo immune response is peptide specific. (Blood. 2011;118(26):6733-6742)

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The structure of the human allo‐ligand HLA‐B*3501 in complex with a cytochrome p450 peptide: Steric hindrance influences TCR allo‐recognition

Cited by 10 publications

References 29 publications

Cross-reactive CD8 ⁺ T-cell immunity between the pandemic H1N1-2009 and H1N1-1918 influenza A viruses

Cross-reactive CD8 ⁺ T-cell immunity between the pandemic H1N1-2009 and H1N1-1918 influenza A viruses

Structural Basis for T Cell Alloreactivity among Three HLA-B14 and HLA-B27 Antigens

Allo-HLA–reactive T cells inducing graft-versus-host disease are single peptide specific

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The structure of the human allo‐ligand HLA‐B*3501 in complex with a cytochrome p450 peptide: Steric hindrance influences TCR allo‐recognition

Cited by 10 publications

References 29 publications

Cross-reactive CD8 + T-cell immunity between the pandemic H1N1-2009 and H1N1-1918 influenza A viruses

Cross-reactive CD8 + T-cell immunity between the pandemic H1N1-2009 and H1N1-1918 influenza A viruses

Structural Basis for T Cell Alloreactivity among Three HLA-B14 and HLA-B27 Antigens

Allo-HLA–reactive T cells inducing graft-versus-host disease are single peptide specific

Contact Info

Product

Resources

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Cross-reactive CD8 ⁺ T-cell immunity between the pandemic H1N1-2009 and H1N1-1918 influenza A viruses

Cross-reactive CD8 ⁺ T-cell immunity between the pandemic H1N1-2009 and H1N1-1918 influenza A viruses