Allelic polymorphism in the T cell receptor and its impact on immune responses

Stephanie Gras, Zhenjun Chen, John J Miles, Yu Chih Liu, Melissa J Bell, Lucy C Sullivan, Lars Kjer-Nielsen, Rebekah M Brennan, Jacqueline M Burrows, Michelle A Neller, Rajiv Khanna, Anthony Wayne Purcell, Andrew G Brooks, James McCluskey, Jamie Rossjohn, Scott R Burrows

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Abstract

In comparison to human leukocyte antigen (HLA) polymorphism, the impact of allelic sequence variation within T cell receptor (TCR) loci is much less understood. Particular TCR loci have been associated with autoimmunity, but the molecular basis for this phenomenon is undefined. We examined the T cell response to an HLA-B*3501-restricted epitope (HPVGEADYFEY) from Epstein-Barr virus (EBV), which is frequently dominated by a TRBV9*01(+) public TCR (TK3). However, the common allelic variant TRBV9*02, which differs by a single amino acid near the CDR2beta loop (Gln55-->His55), was never used in this response. The structure of the TK3 TCR, its allelic variant, and a nonnaturally occurring mutant (Gln55-->Ala55) in complex with HLA-B*3501(HPVGEADYFEY) revealed that the Gln55-->His55 polymorphism affected the charge complementarity at the TCR-peptide-MHC interface, resulting in reduced functional recognition of the cognate and naturally occurring variants of this EBV peptide. Thus, polymorphism in the TCR loci may contribute toward variability in immune responses and the outcome of infection.
Original languageEnglish
Pages (from-to)1555 - 1567
Number of pages13
JournalJournal of Experimental Medicine
Volume207
Issue number7
DOIs
Publication statusPublished - 2010

Cite this

Gras, S., Chen, Z., Miles, J. J., Liu, Y. C., Bell, M. J., Sullivan, L. C., ... Burrows, S. R. (2010). Allelic polymorphism in the T cell receptor and its impact on immune responses. Journal of Experimental Medicine, 207(7), 1555 - 1567. https://doi.org/10.1084/jem.20100603
Gras, Stephanie ; Chen, Zhenjun ; Miles, John J ; Liu, Yu Chih ; Bell, Melissa J ; Sullivan, Lucy C ; Kjer-Nielsen, Lars ; Brennan, Rebekah M ; Burrows, Jacqueline M ; Neller, Michelle A ; Khanna, Rajiv ; Purcell, Anthony Wayne ; Brooks, Andrew G ; McCluskey, James ; Rossjohn, Jamie ; Burrows, Scott R. / Allelic polymorphism in the T cell receptor and its impact on immune responses. In: Journal of Experimental Medicine. 2010 ; Vol. 207, No. 7. pp. 1555 - 1567.
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abstract = "In comparison to human leukocyte antigen (HLA) polymorphism, the impact of allelic sequence variation within T cell receptor (TCR) loci is much less understood. Particular TCR loci have been associated with autoimmunity, but the molecular basis for this phenomenon is undefined. We examined the T cell response to an HLA-B*3501-restricted epitope (HPVGEADYFEY) from Epstein-Barr virus (EBV), which is frequently dominated by a TRBV9*01(+) public TCR (TK3). However, the common allelic variant TRBV9*02, which differs by a single amino acid near the CDR2beta loop (Gln55-->His55), was never used in this response. The structure of the TK3 TCR, its allelic variant, and a nonnaturally occurring mutant (Gln55-->Ala55) in complex with HLA-B*3501(HPVGEADYFEY) revealed that the Gln55-->His55 polymorphism affected the charge complementarity at the TCR-peptide-MHC interface, resulting in reduced functional recognition of the cognate and naturally occurring variants of this EBV peptide. Thus, polymorphism in the TCR loci may contribute toward variability in immune responses and the outcome of infection.",
author = "Stephanie Gras and Zhenjun Chen and Miles, {John J} and Liu, {Yu Chih} and Bell, {Melissa J} and Sullivan, {Lucy C} and Lars Kjer-Nielsen and Brennan, {Rebekah M} and Burrows, {Jacqueline M} and Neller, {Michelle A} and Rajiv Khanna and Purcell, {Anthony Wayne} and Brooks, {Andrew G} and James McCluskey and Jamie Rossjohn and Burrows, {Scott R}",
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Gras, S, Chen, Z, Miles, JJ, Liu, YC, Bell, MJ, Sullivan, LC, Kjer-Nielsen, L, Brennan, RM, Burrows, JM, Neller, MA, Khanna, R, Purcell, AW, Brooks, AG, McCluskey, J, Rossjohn, J & Burrows, SR 2010, 'Allelic polymorphism in the T cell receptor and its impact on immune responses', Journal of Experimental Medicine, vol. 207, no. 7, pp. 1555 - 1567. https://doi.org/10.1084/jem.20100603

Allelic polymorphism in the T cell receptor and its impact on immune responses. / Gras, Stephanie; Chen, Zhenjun; Miles, John J; Liu, Yu Chih; Bell, Melissa J; Sullivan, Lucy C; Kjer-Nielsen, Lars; Brennan, Rebekah M; Burrows, Jacqueline M; Neller, Michelle A; Khanna, Rajiv; Purcell, Anthony Wayne; Brooks, Andrew G; McCluskey, James; Rossjohn, Jamie; Burrows, Scott R.

In: Journal of Experimental Medicine, Vol. 207, No. 7, 2010, p. 1555 - 1567.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Allelic polymorphism in the T cell receptor and its impact on immune responses

AU - Gras, Stephanie

AU - Chen, Zhenjun

AU - Miles, John J

AU - Liu, Yu Chih

AU - Bell, Melissa J

AU - Sullivan, Lucy C

AU - Kjer-Nielsen, Lars

AU - Brennan, Rebekah M

AU - Burrows, Jacqueline M

AU - Neller, Michelle A

AU - Khanna, Rajiv

AU - Purcell, Anthony Wayne

AU - Brooks, Andrew G

AU - McCluskey, James

AU - Rossjohn, Jamie

AU - Burrows, Scott R

PY - 2010

Y1 - 2010

N2 - In comparison to human leukocyte antigen (HLA) polymorphism, the impact of allelic sequence variation within T cell receptor (TCR) loci is much less understood. Particular TCR loci have been associated with autoimmunity, but the molecular basis for this phenomenon is undefined. We examined the T cell response to an HLA-B*3501-restricted epitope (HPVGEADYFEY) from Epstein-Barr virus (EBV), which is frequently dominated by a TRBV9*01(+) public TCR (TK3). However, the common allelic variant TRBV9*02, which differs by a single amino acid near the CDR2beta loop (Gln55-->His55), was never used in this response. The structure of the TK3 TCR, its allelic variant, and a nonnaturally occurring mutant (Gln55-->Ala55) in complex with HLA-B*3501(HPVGEADYFEY) revealed that the Gln55-->His55 polymorphism affected the charge complementarity at the TCR-peptide-MHC interface, resulting in reduced functional recognition of the cognate and naturally occurring variants of this EBV peptide. Thus, polymorphism in the TCR loci may contribute toward variability in immune responses and the outcome of infection.

AB - In comparison to human leukocyte antigen (HLA) polymorphism, the impact of allelic sequence variation within T cell receptor (TCR) loci is much less understood. Particular TCR loci have been associated with autoimmunity, but the molecular basis for this phenomenon is undefined. We examined the T cell response to an HLA-B*3501-restricted epitope (HPVGEADYFEY) from Epstein-Barr virus (EBV), which is frequently dominated by a TRBV9*01(+) public TCR (TK3). However, the common allelic variant TRBV9*02, which differs by a single amino acid near the CDR2beta loop (Gln55-->His55), was never used in this response. The structure of the TK3 TCR, its allelic variant, and a nonnaturally occurring mutant (Gln55-->Ala55) in complex with HLA-B*3501(HPVGEADYFEY) revealed that the Gln55-->His55 polymorphism affected the charge complementarity at the TCR-peptide-MHC interface, resulting in reduced functional recognition of the cognate and naturally occurring variants of this EBV peptide. Thus, polymorphism in the TCR loci may contribute toward variability in immune responses and the outcome of infection.

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DO - 10.1084/jem.20100603

M3 - Article

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JO - Journal of Experimental Medicine

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