Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4

Omar S. Qureshi; Yong Zheng; Kyoko Nakamura; Kesley Attridge; Claire Manzotti; Emily M. Schmidt; Jennifer Baker; Louisa E. Jeffery; Satdip Kaur; Zoe Briggs; Tie Z. Hou; Clare E. Futter; Graham Anderson; Lucy S.K. Walker; David M. Sansom

doi:10.1126/science.1202947

Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4

Omar S. Qureshi, Yong Zheng, Kyoko Nakamura, Kesley Attridge, Claire Manzotti, Emily M. Schmidt, Jennifer Baker, Louisa E. Jeffery, Satdip Kaur, Zoe Briggs, Tie Z. Hou, Clare E. Futter, Graham Anderson, Lucy S.K. Walker, David M. Sansom

College of Health and Life Sciences

Research output: Contribution to journal › Article › peer-review

Abstract

Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an essential negative regulator of T cell immune responses whose mechanism of action is the subject of debate. CTLA-4 shares two ligands (CD80 and CD86) with a stimulatory receptor, CD28. Here, we show that CTLA-4 can capture its ligands from opposing cells by a process of trans-endocytosis. After removal, these costimulatory ligands are degraded inside CTLA-4-expressing cells, resulting in impaired costimulation via CD28. Acquisition of CD86 from antigen-presenting cells is stimulated by T cell receptor engagement and observed in vitro and in vivo. These data reveal a mechanism of immune regulation in which CTLA-4 acts as an effector molecule to inhibit CD28 costimulation by the cell-extrinsic depletion of ligands, accounting for many of the known features of the CD28-CTLA-4 system.

Original language	English
Pages (from-to)	600-603
Number of pages	4
Journal	Science
Volume	332
Issue number	6029
DOIs	https://doi.org/10.1126/science.1202947
Publication status	Published - 29 Apr 2011

Bibliographical note

Keywords

antigen
antigens
CHO cells
cricetinae
cricetulus
Dendritic cells
endocytosis
Jurkat cells
ligands
Lymphocyte activation
T-Cell
biological models
ovalbumin
receptors
recombinant fusion proteins
T-lymphocyte subsets
regulatory T-lymphocytes

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10.1126/science.1202947

Trans-endocytosis of CD80 and CD86: a molecular basis for the cell extrinsic function of CTLA-4
Copyright © 2011, American Association for the Advancement of Science
Accepted author manuscript, 1.74 MB

Cite this

Qureshi, O. S., Zheng, Y., Nakamura, K., Attridge, K., Manzotti, C., Schmidt, E. M., Baker, J., Jeffery, L. E., Kaur, S., Briggs, Z., Hou, T. Z., Futter, C. E., Anderson, G., Walker, L. S. K., & Sansom, D. M. (2011). Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science, 332(6029), 600-603. https://doi.org/10.1126/science.1202947

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title = "Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4",

abstract = "Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an essential negative regulator of T cell immune responses whose mechanism of action is the subject of debate. CTLA-4 shares two ligands (CD80 and CD86) with a stimulatory receptor, CD28. Here, we show that CTLA-4 can capture its ligands from opposing cells by a process of trans-endocytosis. After removal, these costimulatory ligands are degraded inside CTLA-4-expressing cells, resulting in impaired costimulation via CD28. Acquisition of CD86 from antigen-presenting cells is stimulated by T cell receptor engagement and observed in vitro and in vivo. These data reveal a mechanism of immune regulation in which CTLA-4 acts as an effector molecule to inhibit CD28 costimulation by the cell-extrinsic depletion of ligands, accounting for many of the known features of the CD28-CTLA-4 system.",

keywords = "antigen, antigens, CHO cells, cricetinae, cricetulus, Dendritic cells, endocytosis, Jurkat cells, ligands, Lymphocyte activation, T-Cell, biological models, ovalbumin, receptors, recombinant fusion proteins, T-lymphocyte subsets, regulatory T-lymphocytes",

author = "Qureshi, {Omar S.} and Yong Zheng and Kyoko Nakamura and Kesley Attridge and Claire Manzotti and Schmidt, {Emily M.} and Jennifer Baker and Jeffery, {Louisa E.} and Satdip Kaur and Zoe Briggs and Hou, {Tie Z.} and Futter, {Clare E.} and Graham Anderson and Walker, {Lucy S.K.} and Sansom, {David M.}",

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day = "29",

doi = "10.1126/science.1202947",

language = "English",

volume = "332",

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T2 - a molecular basis for the cell-extrinsic function of CTLA-4

AU - Qureshi, Omar S.

AU - Zheng, Yong

AU - Nakamura, Kyoko

AU - Attridge, Kesley

AU - Manzotti, Claire

AU - Schmidt, Emily M.

AU - Baker, Jennifer

AU - Jeffery, Louisa E.

AU - Kaur, Satdip

AU - Briggs, Zoe

AU - Hou, Tie Z.

AU - Futter, Clare E.

AU - Anderson, Graham

AU - Walker, Lucy S.K.

AU - Sansom, David M.

PY - 2011/4/29

Y1 - 2011/4/29

N2 - Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an essential negative regulator of T cell immune responses whose mechanism of action is the subject of debate. CTLA-4 shares two ligands (CD80 and CD86) with a stimulatory receptor, CD28. Here, we show that CTLA-4 can capture its ligands from opposing cells by a process of trans-endocytosis. After removal, these costimulatory ligands are degraded inside CTLA-4-expressing cells, resulting in impaired costimulation via CD28. Acquisition of CD86 from antigen-presenting cells is stimulated by T cell receptor engagement and observed in vitro and in vivo. These data reveal a mechanism of immune regulation in which CTLA-4 acts as an effector molecule to inhibit CD28 costimulation by the cell-extrinsic depletion of ligands, accounting for many of the known features of the CD28-CTLA-4 system.

AB - Cytotoxic T lymphocyte antigen 4 (CTLA-4) is an essential negative regulator of T cell immune responses whose mechanism of action is the subject of debate. CTLA-4 shares two ligands (CD80 and CD86) with a stimulatory receptor, CD28. Here, we show that CTLA-4 can capture its ligands from opposing cells by a process of trans-endocytosis. After removal, these costimulatory ligands are degraded inside CTLA-4-expressing cells, resulting in impaired costimulation via CD28. Acquisition of CD86 from antigen-presenting cells is stimulated by T cell receptor engagement and observed in vitro and in vivo. These data reveal a mechanism of immune regulation in which CTLA-4 acts as an effector molecule to inhibit CD28 costimulation by the cell-extrinsic depletion of ligands, accounting for many of the known features of the CD28-CTLA-4 system.

KW - antigen

KW - antigens

KW - CHO cells

KW - cricetinae

KW - cricetulus

KW - Dendritic cells

KW - endocytosis

KW - Jurkat cells

KW - ligands

KW - Lymphocyte activation

KW - T-Cell

KW - biological models

KW - ovalbumin

KW - receptors

KW - recombinant fusion proteins

KW - T-lymphocyte subsets

KW - regulatory T-lymphocytes

UR - http://science.sciencemag.org/content/332/6029/600

U2 - 10.1126/science.1202947

DO - 10.1126/science.1202947

M3 - Article

C2 - 21474713

SN - 0036-8075

VL - 332

SP - 600

EP - 603

JO - Science

JF - Science

IS - 6029

ER -

Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4

Abstract

Bibliographical note

Keywords

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