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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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Related in: MedlinePlus

DM1–pMHC interactions compared with the LC13–pMHC structure, revealing similar positioning of the CDRα loops. (a) DM1 TCR “footprint” on HLA-B*4405EENL. HLA-B*4405EENL (gray) is shown in surface representation. The pMHC residues are colored according to the relevant contacting CDR loop. The positions of the CDR loops are also shown (CDR1α, orange; CDR2α, yellow; CDR3α, red; CDR1β, slate; CDR2β, green; CDR3β, teal). (b) LC13 footprint on HLA-B*0801FLR. HLA-B*0801FLR (gray) is shown in surface representation. The pMHC residues are colored according to the relevant contacting CDR loop (CDR1α, orange; CDR2α, yellow; CDR3α, red; CDR1β, slate; CDR2β, green; CDR3β, teal). The LC13 CDR loops are shown in gray. (c) Similar positioning of the CDR1α loops (CDR1α, orange; CDR2α, yellow; CDR3α, red) of DM1 compared with LC13 (gray) allowed conservation of interactions with residues E154, Q155, and A158 on the α2 helix. (d) Although the positioning of the Vβ loops of the two TCRs was divergent, the packing of Q50β of the CDR2β loop of DM1 (green) and LC13 (gray) between Q72 and E76 was maintained.
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fig6: DM1–pMHC interactions compared with the LC13–pMHC structure, revealing similar positioning of the CDRα loops. (a) DM1 TCR “footprint” on HLA-B*4405EENL. HLA-B*4405EENL (gray) is shown in surface representation. The pMHC residues are colored according to the relevant contacting CDR loop. The positions of the CDR loops are also shown (CDR1α, orange; CDR2α, yellow; CDR3α, red; CDR1β, slate; CDR2β, green; CDR3β, teal). (b) LC13 footprint on HLA-B*0801FLR. HLA-B*0801FLR (gray) is shown in surface representation. The pMHC residues are colored according to the relevant contacting CDR loop (CDR1α, orange; CDR2α, yellow; CDR3α, red; CDR1β, slate; CDR2β, green; CDR3β, teal). The LC13 CDR loops are shown in gray. (c) Similar positioning of the CDR1α loops (CDR1α, orange; CDR2α, yellow; CDR3α, red) of DM1 compared with LC13 (gray) allowed conservation of interactions with residues E154, Q155, and A158 on the α2 helix. (d) Although the positioning of the Vβ loops of the two TCRs was divergent, the packing of Q50β of the CDR2β loop of DM1 (green) and LC13 (gray) between Q72 and E76 was maintained.

Mentions: The DM1 TCR (TRAV26-1*02;TRAJ13*02;TRBV7-9*01;TRBJ2-1*01;TRBD1*01) uses Vα and Vβ gene segments similar to those of the LC13 TCR (TRAV26-2*01;TRAJ52*01/TRBV7-8*03;TRBJ2-7*01;TRBD1/2), which interacts with HLA-B*0801 bound to the FLRGRAYGL antigen (21), as well as HLA-B44 when bound to an alloantigen. The DM1 and LC13 TCRs share similarities in the CDR1α, CDR2α, CDR1β, and CDR2β loops (for sequence conservation see Table S2, available at http://www.jem.org/cgi/content/full/jem.20082136/DC1) (22, 23). In comparison to the LC13 footprint on HLA-B8FLRGRAYGL, the CDR1α and CDR2α loops are in roughly equivalent locations, although the positioning of the corresponding loops in the Vβ domain is more divergent (Fig. 6, a and b). From examination of all known TCR–pMHC co-crystal structures, it has been noted that TCRs often use a Tyr/Phe in the CDR1α to interact with position 155 (24). Indeed, both DM1 and LC13 use an aromatic residue to contact Gln155, as well as a Gly 30α to contact Ala158 (Fig. 6 c). Moreover, although CDR2α played a minor role in interacting with HLA-B44, both the DM1 TCR and the LC13 TCR use a Leu at the same position in CDR2α to conserve the interaction with Glu154 (Fig. 6 c). Although it has been suggested that a Ser in the CDR2α loop will contact the MHC at position 154–155 (24), this has not been observed in the DM1 TCR complex or other TCR–pMHC complexes. Although the positioning of the CDR2β loops is quite different, the sandwiching of Gln 50β between Gln72 and Glu76 is maintained (Fig. 6 d). Accordingly, there are some similarities, as well as notable differences, in the manner in which very similar Vα and Vβ gene segments interact with differing pMHC landscapes.


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–pMHC interactions compared with the LC13–pMHC structure, revealing similar positioning of the CDRα loops. (a) DM1 TCR “footprint” on HLA-B*4405EENL. HLA-B*4405EENL (gray) is shown in surface representation. The pMHC residues are colored according to the relevant contacting CDR loop. The positions of the CDR loops are also shown (CDR1α, orange; CDR2α, yellow; CDR3α, red; CDR1β, slate; CDR2β, green; CDR3β, teal). (b) LC13 footprint on HLA-B*0801FLR. HLA-B*0801FLR (gray) is shown in surface representation. The pMHC residues are colored according to the relevant contacting CDR loop (CDR1α, orange; CDR2α, yellow; CDR3α, red; CDR1β, slate; CDR2β, green; CDR3β, teal). The LC13 CDR loops are shown in gray. (c) Similar positioning of the CDR1α loops (CDR1α, orange; CDR2α, yellow; CDR3α, red) of DM1 compared with LC13 (gray) allowed conservation of interactions with residues E154, Q155, and A158 on the α2 helix. (d) Although the positioning of the Vβ loops of the two TCRs was divergent, the packing of Q50β of the CDR2β loop of DM1 (green) and LC13 (gray) between Q72 and E76 was maintained.
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Related In: Results  -  Collection

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fig6: DM1–pMHC interactions compared with the LC13–pMHC structure, revealing similar positioning of the CDRα loops. (a) DM1 TCR “footprint” on HLA-B*4405EENL. HLA-B*4405EENL (gray) is shown in surface representation. The pMHC residues are colored according to the relevant contacting CDR loop. The positions of the CDR loops are also shown (CDR1α, orange; CDR2α, yellow; CDR3α, red; CDR1β, slate; CDR2β, green; CDR3β, teal). (b) LC13 footprint on HLA-B*0801FLR. HLA-B*0801FLR (gray) is shown in surface representation. The pMHC residues are colored according to the relevant contacting CDR loop (CDR1α, orange; CDR2α, yellow; CDR3α, red; CDR1β, slate; CDR2β, green; CDR3β, teal). The LC13 CDR loops are shown in gray. (c) Similar positioning of the CDR1α loops (CDR1α, orange; CDR2α, yellow; CDR3α, red) of DM1 compared with LC13 (gray) allowed conservation of interactions with residues E154, Q155, and A158 on the α2 helix. (d) Although the positioning of the Vβ loops of the two TCRs was divergent, the packing of Q50β of the CDR2β loop of DM1 (green) and LC13 (gray) between Q72 and E76 was maintained.
Mentions: The DM1 TCR (TRAV26-1*02;TRAJ13*02;TRBV7-9*01;TRBJ2-1*01;TRBD1*01) uses Vα and Vβ gene segments similar to those of the LC13 TCR (TRAV26-2*01;TRAJ52*01/TRBV7-8*03;TRBJ2-7*01;TRBD1/2), which interacts with HLA-B*0801 bound to the FLRGRAYGL antigen (21), as well as HLA-B44 when bound to an alloantigen. The DM1 and LC13 TCRs share similarities in the CDR1α, CDR2α, CDR1β, and CDR2β loops (for sequence conservation see Table S2, available at http://www.jem.org/cgi/content/full/jem.20082136/DC1) (22, 23). In comparison to the LC13 footprint on HLA-B8FLRGRAYGL, the CDR1α and CDR2α loops are in roughly equivalent locations, although the positioning of the corresponding loops in the Vβ domain is more divergent (Fig. 6, a and b). From examination of all known TCR–pMHC co-crystal structures, it has been noted that TCRs often use a Tyr/Phe in the CDR1α to interact with position 155 (24). Indeed, both DM1 and LC13 use an aromatic residue to contact Gln155, as well as a Gly 30α to contact Ala158 (Fig. 6 c). Moreover, although CDR2α played a minor role in interacting with HLA-B44, both the DM1 TCR and the LC13 TCR use a Leu at the same position in CDR2α to conserve the interaction with Glu154 (Fig. 6 c). Although it has been suggested that a Ser in the CDR2α loop will contact the MHC at position 154–155 (24), this has not been observed in the DM1 TCR complex or other TCR–pMHC complexes. Although the positioning of the CDR2β loops is quite different, the sandwiching of Gln 50β between Gln72 and Glu76 is maintained (Fig. 6 d). Accordingly, there are some similarities, as well as notable differences, in the manner in which very similar Vα and Vβ gene segments interact with differing pMHC landscapes.

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