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A Transendocytosis Model of CTLA-4 Function Predicts Its Suppressive Behavior on Regulatory T Cells

Hou, TZ; Qureshi, OS; Wang, CJ; Baker, J; Young, SP; Walker, LSK; Sansom, DM; (2015) A Transendocytosis Model of CTLA-4 Function Predicts Its Suppressive Behavior on Regulatory T Cells. Journal of Immunology , 194 (5) pp. 2148-2159. 10.4049/jimmunol.1401876.

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Abstract

Manipulation of the CD28/CTLA-4 pathway is at the heart of a number of immunomodulatory approaches used in both autoimmunity and cancer. Although it is clear that CTLA-4 is a critical regulator of T cell responses, the immunological contexts in which CTLA-4 controls immune responses are not well defined. In this study, we show that whereas CD80/CD86-dependent activation of resting human T cells caused extensive T cell proliferation and robust CTLA-4 expression, in this context CTLA-4 blocking Abs had no impact on the response. In contrast, in settings where CTLA-4+ cells were present as “regulators,” inhibition of resting T cell responses was dependent on CTLA-4 expression and specifically related to the number of APC. At low numbers of APC or low levels of ligand, CTLA-4–dependent suppression was highly effective whereas at higher APC numbers or high levels of ligand, inhibition was lost. Accordingly, the degree of suppression correlated with the level of CD86 expression remaining on the APC. These data reveal clear rules for the inhibitory function of CTLA-4 on regulatory T cells, which are predicted by its ability to remove ligands from APC.

Type: Article
Title: A Transendocytosis Model of CTLA-4 Function Predicts Its Suppressive Behavior on Regulatory T Cells
DOI: 10.4049/jimmunol.1401876
Publisher version: https://doi.org/10.4049/jimmunol.1401876
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Science & Technology, Life Sciences & Biomedicine, Immunology, MULTIORGAN TISSUE DESTRUCTION, DENDRITIC CELLS, CUTTING EDGE, COSTIMULATORY MOLECULES, AUTOIMMUNE-DISEASE, CYTOPLASMIC DOMAIN, IMMUNE REGULATION, CO-STIMULATION, IN-VIVO, ACTIVATION
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
URI: https://discovery.ucl.ac.uk/id/eprint/1467747
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