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Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition.

Archbold JK, Macdonald WA, Gras S, Ely LK, Miles JJ, Bell MJ, Brennan RM, Beddoe T, Wilce MC, Clements CS, Purcell AW, McCluskey J, Burrows SR, Rossjohn J - J. Exp. Med. (2009)

Bottom Line: T cell-mediated immunity to an Epstein-Barr virus determinant (EENLLDFVRF) is enhanced when HLA-B*4405 was the presenting allotype compared with HLA-B*4402 or HLA-B*4403, each of which differ by just one amino acid.The structure of the TCR-HLA-B*4405(EENLLDFVRF) complex revealed that peptide flexibility was a critical parameter in enabling preferential engagement with HLA-B*4405 in comparison to HLA-B*4402/03.Accordingly, major histocompatibility complex (MHC) polymorphism can alter the dynamics of the peptide-MHC landscape, resulting in fine-tuning of T cell responses between closely related allotypes.

View Article: PubMed Central - PubMed

Affiliation: The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.

ABSTRACT
Human leukocyte antigen (HLA) gene polymorphism plays a critical role in protective immunity, disease susceptibility, autoimmunity, and drug hypersensitivity, yet the basis of how HLA polymorphism influences T cell receptor (TCR) recognition is unclear. We examined how a natural micropolymorphism in HLA-B44, an important and large HLA allelic family, affected antigen recognition. T cell-mediated immunity to an Epstein-Barr virus determinant (EENLLDFVRF) is enhanced when HLA-B*4405 was the presenting allotype compared with HLA-B*4402 or HLA-B*4403, each of which differ by just one amino acid. The micropolymorphism in these HLA-B44 allotypes altered the mode of binding and dynamics of the bound viral epitope. The structure of the TCR-HLA-B*4405(EENLLDFVRF) complex revealed that peptide flexibility was a critical parameter in enabling preferential engagement with HLA-B*4405 in comparison to HLA-B*4402/03. Accordingly, major histocompatibility complex (MHC) polymorphism can alter the dynamics of the peptide-MHC landscape, resulting in fine-tuning of T cell responses between closely related allotypes.

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DM1 interactions with HLA-B*4405EENL. (a) Interactions with the HLA-B*4405 heavy chain mediated by the Vα domain of the DM1 TCR (CDR1α, orange; CDR2α, yellow; CDR3α, red; HLA-B*4405 heavy chain, gray; EENL epitope, blue). (b) Interactions with the HLA-B*4405 heavy chain mediated by the Vβ domain of the DM1 TCR (CDR1β, slate; CDR2β, green; CDR3β, teal; HLA-B*4405 heavy chain, gray; EENL epitope, blue).
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fig5: DM1 interactions with HLA-B*4405EENL. (a) Interactions with the HLA-B*4405 heavy chain mediated by the Vα domain of the DM1 TCR (CDR1α, orange; CDR2α, yellow; CDR3α, red; HLA-B*4405 heavy chain, gray; EENL epitope, blue). (b) Interactions with the HLA-B*4405 heavy chain mediated by the Vβ domain of the DM1 TCR (CDR1β, slate; CDR2β, green; CDR3β, teal; HLA-B*4405 heavy chain, gray; EENL epitope, blue).

Mentions: The CDR1α and CDR2α loops exclusively contacted residues spanning 155–163 from the α2 helix (Table II and Fig. 5 a). Asn 31α nestled in a shallow pocket that was flanked by Leu163 and Gln155, the latter of which also interacted with Tyr 33α (Fig. 5 a). Interestingly, Gln155, previously described as a gatekeeper residue, shifted conformation upon TCR ligation to form interactions with CDR1α as well as the peptide. The CDR2α played a limited role in interacting with HLA-B44 (Table II and Fig. 5 a), with Leu 57α forming vdw interactions with Glu154 and Arg151, the latter of which also moved to salt bridge with framework residue Glu 67α (Table II and Fig. 5 a). The CDR1β and CDR2β contacted residues spanning 69–76 of the α1 helix (Table II), with the role of CDR1β being restricted to interacting with Thr73 and Glu76 (Fig. 5 b), a residue that moved ∼2.5 Å to contact the CDR1β and CDR2β loops. The CDR2β loop comprised several polar residues (Gln 57β, Asn 58β, and Glu 59β) and, accordingly, was observed to form several H bonds to the α1 helix of HLA-B*4405 (Fig. 5 b).


Natural micropolymorphism in human leukocyte antigens provides a basis for genetic control of antigen recognition.

Archbold JK, Macdonald WA, Gras S, Ely LK, Miles JJ, Bell MJ, Brennan RM, Beddoe T, Wilce MC, Clements CS, Purcell AW, McCluskey J, Burrows SR, Rossjohn J - J. Exp. Med. (2009)

DM1 interactions with HLA-B*4405EENL. (a) Interactions with the HLA-B*4405 heavy chain mediated by the Vα domain of the DM1 TCR (CDR1α, orange; CDR2α, yellow; CDR3α, red; HLA-B*4405 heavy chain, gray; EENL epitope, blue). (b) Interactions with the HLA-B*4405 heavy chain mediated by the Vβ domain of the DM1 TCR (CDR1β, slate; CDR2β, green; CDR3β, teal; HLA-B*4405 heavy chain, gray; EENL epitope, blue).
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Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2626662&req=5

fig5: DM1 interactions with HLA-B*4405EENL. (a) Interactions with the HLA-B*4405 heavy chain mediated by the Vα domain of the DM1 TCR (CDR1α, orange; CDR2α, yellow; CDR3α, red; HLA-B*4405 heavy chain, gray; EENL epitope, blue). (b) Interactions with the HLA-B*4405 heavy chain mediated by the Vβ domain of the DM1 TCR (CDR1β, slate; CDR2β, green; CDR3β, teal; HLA-B*4405 heavy chain, gray; EENL epitope, blue).
Mentions: The CDR1α and CDR2α loops exclusively contacted residues spanning 155–163 from the α2 helix (Table II and Fig. 5 a). Asn 31α nestled in a shallow pocket that was flanked by Leu163 and Gln155, the latter of which also interacted with Tyr 33α (Fig. 5 a). Interestingly, Gln155, previously described as a gatekeeper residue, shifted conformation upon TCR ligation to form interactions with CDR1α as well as the peptide. The CDR2α played a limited role in interacting with HLA-B44 (Table II and Fig. 5 a), with Leu 57α forming vdw interactions with Glu154 and Arg151, the latter of which also moved to salt bridge with framework residue Glu 67α (Table II and Fig. 5 a). The CDR1β and CDR2β contacted residues spanning 69–76 of the α1 helix (Table II), with the role of CDR1β being restricted to interacting with Thr73 and Glu76 (Fig. 5 b), a residue that moved ∼2.5 Å to contact the CDR1β and CDR2β loops. The CDR2β loop comprised several polar residues (Gln 57β, Asn 58β, and Glu 59β) and, accordingly, was observed to form several H bonds to the α1 helix of HLA-B*4405 (Fig. 5 b).

Bottom Line: T cell-mediated immunity to an Epstein-Barr virus determinant (EENLLDFVRF) is enhanced when HLA-B*4405 was the presenting allotype compared with HLA-B*4402 or HLA-B*4403, each of which differ by just one amino acid.The structure of the TCR-HLA-B*4405(EENLLDFVRF) complex revealed that peptide flexibility was a critical parameter in enabling preferential engagement with HLA-B*4405 in comparison to HLA-B*4402/03.Accordingly, major histocompatibility complex (MHC) polymorphism can alter the dynamics of the peptide-MHC landscape, resulting in fine-tuning of T cell responses between closely related allotypes.

View Article: PubMed Central - PubMed

Affiliation: The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.

ABSTRACT
Human leukocyte antigen (HLA) gene polymorphism plays a critical role in protective immunity, disease susceptibility, autoimmunity, and drug hypersensitivity, yet the basis of how HLA polymorphism influences T cell receptor (TCR) recognition is unclear. We examined how a natural micropolymorphism in HLA-B44, an important and large HLA allelic family, affected antigen recognition. T cell-mediated immunity to an Epstein-Barr virus determinant (EENLLDFVRF) is enhanced when HLA-B*4405 was the presenting allotype compared with HLA-B*4402 or HLA-B*4403, each of which differ by just one amino acid. The micropolymorphism in these HLA-B44 allotypes altered the mode of binding and dynamics of the bound viral epitope. The structure of the TCR-HLA-B*4405(EENLLDFVRF) complex revealed that peptide flexibility was a critical parameter in enabling preferential engagement with HLA-B*4405 in comparison to HLA-B*4402/03. Accordingly, major histocompatibility complex (MHC) polymorphism can alter the dynamics of the peptide-MHC landscape, resulting in fine-tuning of T cell responses between closely related allotypes.

Show MeSH
Related in: MedlinePlus