Enhanced immunogenicity of CTL antigens through mutation of the CD8 binding MHC class I invariant region

Linda Wooldridge; Anya Lissina; Jonathan Vernazza; Emma Gostick; Bruno Laugel; Sarah L Hutchinson; Fareed Mirza; P Rod Dunbar; Jonathan M Boulter; Meir Glick; Vincenzo Cerundolo; Hugo A van den Berg; David A Price; Andrew K Sewell

doi:10.1002/eji.200636765

Enhanced immunogenicity of CTL antigens through mutation of the CD8 binding MHC class I invariant region

Linda Wooldridge, Anya Lissina, Jonathan Vernazza, Emma Gostick, Bruno Laugel, Sarah L Hutchinson, Fareed Mirza, P Rod Dunbar, Jonathan M Boulter, Meir Glick, Vincenzo Cerundolo, Hugo A van den Berg, David A Price, Andrew K Sewell

Research output: Contribution to journal › Article (Academic Journal) › peer-review

56 Citations (Scopus)

Abstract

CD8(+) cytotoxic T lymphocytes (CTL) are key determinants of immunity to intracellular pathogens and neoplastic cells. Recognition of specific antigens in the form of peptide-MHC class I complexes (pMHCI) presented on the target cell surface is mediated by T cell receptor (TCR) engagement. The CD8 coreceptor binds to invariant domains of pMHCI and facilitates antigen recognition. Here, we investigate the biological effects of a Q115E substitution in the alpha2 domain of human leukocyte antigen (HLA)-A*0201 that enhances CD8 binding by approximately 50% without altering TCR/pMHCI interactions. Soluble and cell surface-expressed forms of Q115E HLA-A*0201 exhibit enhanced recognition by CTL without loss of specificity. These CD8-enhanced antigens induce greater CD3 zeta chain phosphorylation in cognate CTL leading to substantial increases in cytokine production, proliferation and priming of naive T cells. This effect provides a fundamental new mechanism with which to enhance cellular immunity to specific T cell antigens.

Original language	English
Pages (from-to)	1323-33
Number of pages	11
Journal	European Journal of Immunology
Volume	37
Issue number	5
DOIs	https://doi.org/10.1002/eji.200636765
Publication status	Published - May 2007

Keywords

Amino Acid Sequence
Antigen Presentation
Antigens, CD8
Epitopes, T-Lymphocyte
HLA-A Antigens
HLA-A2 Antigen
Humans
Lymphocyte Activation
Molecular Sequence Data
Mutation
Protein Structure, Quaternary
Receptors, Antigen, T-Cell
Surface Plasmon Resonance
T-Lymphocytes, Cytotoxic
Transfection

Access to Document

10.1002/eji.200636765

Handle.net

Persistent link

Cite this

Wooldridge, L., Lissina, A., Vernazza, J., Gostick, E., Laugel, B., Hutchinson, S. L., Mirza, F., Dunbar, P. R., Boulter, J. M., Glick, M., Cerundolo, V., van den Berg, H. A., Price, D. A., & Sewell, A. K. (2007). Enhanced immunogenicity of CTL antigens through mutation of the CD8 binding MHC class I invariant region. European Journal of Immunology, 37(5), 1323-33. https://doi.org/10.1002/eji.200636765

@article{75016e587b424243be7a2f78dd173bf5,

title = "Enhanced immunogenicity of CTL antigens through mutation of the CD8 binding MHC class I invariant region",

abstract = "CD8(+) cytotoxic T lymphocytes (CTL) are key determinants of immunity to intracellular pathogens and neoplastic cells. Recognition of specific antigens in the form of peptide-MHC class I complexes (pMHCI) presented on the target cell surface is mediated by T cell receptor (TCR) engagement. The CD8 coreceptor binds to invariant domains of pMHCI and facilitates antigen recognition. Here, we investigate the biological effects of a Q115E substitution in the alpha2 domain of human leukocyte antigen (HLA)-A*0201 that enhances CD8 binding by approximately 50% without altering TCR/pMHCI interactions. Soluble and cell surface-expressed forms of Q115E HLA-A*0201 exhibit enhanced recognition by CTL without loss of specificity. These CD8-enhanced antigens induce greater CD3 zeta chain phosphorylation in cognate CTL leading to substantial increases in cytokine production, proliferation and priming of naive T cells. This effect provides a fundamental new mechanism with which to enhance cellular immunity to specific T cell antigens.",

keywords = "Amino Acid Sequence, Antigen Presentation, Antigens, CD8, Epitopes, T-Lymphocyte, HLA-A Antigens, HLA-A2 Antigen, Humans, Lymphocyte Activation, Molecular Sequence Data, Mutation, Protein Structure, Quaternary, Receptors, Antigen, T-Cell, Surface Plasmon Resonance, T-Lymphocytes, Cytotoxic, Transfection",

author = "Linda Wooldridge and Anya Lissina and Jonathan Vernazza and Emma Gostick and Bruno Laugel and Hutchinson, {Sarah L} and Fareed Mirza and Dunbar, {P Rod} and Boulter, {Jonathan M} and Meir Glick and Vincenzo Cerundolo and {van den Berg}, {Hugo A} and Price, {David A} and Sewell, {Andrew K}",

year = "2007",

month = may,

doi = "10.1002/eji.200636765",

language = "English",

volume = "37",

pages = "1323--33",

journal = "European Journal of Immunology",

issn = "0014-2980",

publisher = "Wiley-Blackwell",

number = "5",

}

Wooldridge, L, Lissina, A, Vernazza, J, Gostick, E, Laugel, B, Hutchinson, SL, Mirza, F, Dunbar, PR, Boulter, JM, Glick, M, Cerundolo, V, van den Berg, HA, Price, DA & Sewell, AK 2007, 'Enhanced immunogenicity of CTL antigens through mutation of the CD8 binding MHC class I invariant region', European Journal of Immunology, vol. 37, no. 5, pp. 1323-33. https://doi.org/10.1002/eji.200636765

TY - JOUR

T1 - Enhanced immunogenicity of CTL antigens through mutation of the CD8 binding MHC class I invariant region

AU - Wooldridge, Linda

AU - Lissina, Anya

AU - Vernazza, Jonathan

AU - Gostick, Emma

AU - Laugel, Bruno

AU - Hutchinson, Sarah L

AU - Mirza, Fareed

AU - Dunbar, P Rod

AU - Boulter, Jonathan M

AU - Glick, Meir

AU - Cerundolo, Vincenzo

AU - van den Berg, Hugo A

AU - Price, David A

AU - Sewell, Andrew K

PY - 2007/5

Y1 - 2007/5

N2 - CD8(+) cytotoxic T lymphocytes (CTL) are key determinants of immunity to intracellular pathogens and neoplastic cells. Recognition of specific antigens in the form of peptide-MHC class I complexes (pMHCI) presented on the target cell surface is mediated by T cell receptor (TCR) engagement. The CD8 coreceptor binds to invariant domains of pMHCI and facilitates antigen recognition. Here, we investigate the biological effects of a Q115E substitution in the alpha2 domain of human leukocyte antigen (HLA)-A*0201 that enhances CD8 binding by approximately 50% without altering TCR/pMHCI interactions. Soluble and cell surface-expressed forms of Q115E HLA-A*0201 exhibit enhanced recognition by CTL without loss of specificity. These CD8-enhanced antigens induce greater CD3 zeta chain phosphorylation in cognate CTL leading to substantial increases in cytokine production, proliferation and priming of naive T cells. This effect provides a fundamental new mechanism with which to enhance cellular immunity to specific T cell antigens.

AB - CD8(+) cytotoxic T lymphocytes (CTL) are key determinants of immunity to intracellular pathogens and neoplastic cells. Recognition of specific antigens in the form of peptide-MHC class I complexes (pMHCI) presented on the target cell surface is mediated by T cell receptor (TCR) engagement. The CD8 coreceptor binds to invariant domains of pMHCI and facilitates antigen recognition. Here, we investigate the biological effects of a Q115E substitution in the alpha2 domain of human leukocyte antigen (HLA)-A*0201 that enhances CD8 binding by approximately 50% without altering TCR/pMHCI interactions. Soluble and cell surface-expressed forms of Q115E HLA-A*0201 exhibit enhanced recognition by CTL without loss of specificity. These CD8-enhanced antigens induce greater CD3 zeta chain phosphorylation in cognate CTL leading to substantial increases in cytokine production, proliferation and priming of naive T cells. This effect provides a fundamental new mechanism with which to enhance cellular immunity to specific T cell antigens.

KW - Amino Acid Sequence

KW - Antigen Presentation

KW - Antigens, CD8

KW - Epitopes, T-Lymphocyte

KW - HLA-A Antigens

KW - HLA-A2 Antigen

KW - Humans

KW - Lymphocyte Activation

KW - Molecular Sequence Data

KW - Mutation

KW - Protein Structure, Quaternary

KW - Receptors, Antigen, T-Cell

KW - Surface Plasmon Resonance

KW - T-Lymphocytes, Cytotoxic

KW - Transfection

U2 - 10.1002/eji.200636765

DO - 10.1002/eji.200636765

M3 - Article (Academic Journal)

C2 - 17429845

SN - 0014-2980

VL - 37

SP - 1323

EP - 1333

JO - European Journal of Immunology

JF - European Journal of Immunology

IS - 5

ER -

Enhanced immunogenicity of CTL antigens through mutation of the CD8 binding MHC class I invariant region

Abstract

Keywords

Access to Document

Handle.net

Fingerprint

Cite this