title: A transendocytosis model of CTLA-4 function predicts its suppressive behavior on regulatory T cells.
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.
authors: Division of Infection and Immunity, Department of Immunology, Institute of Immunity and Transplantation, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom; and.
authors: Tie Zheng
authors: TZ
authors: Hou
authors: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
authors: Omar S
authors: OS
authors: Qureshi
authors: Division of Infection and Immunity, Department of Immunology, Institute of Immunity and Transplantation, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom; and.
authors: Chun Jing
authors: CJ
authors: Wang
authors: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
authors: Jennifer
authors: J
authors: Baker
authors: School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
authors: Stephen P
authors: SP
authors: Young
authors: Division of Infection and Immunity, Department of Immunology, Institute of Immunity and Transplantation, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom; and.
authors: Lucy S K
authors: LS
authors: Walker
authors: Division of Infection and Immunity, Department of Immunology, Institute of Immunity and Transplantation, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom; and d.sansom@ucl.ac.uk.
authors: David M
authors: DM
authors: Sansom
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology; D051940:B7-2 Antigen / Q000235:genetics / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics / Q000276:immunology; D016466:CHO Cells; D060908:CTLA-4 Antigen / Q000235:genetics / Q000276:immunology; D002452:Cell Count; D049109:Cell Proliferation; D003412:Cricetulus; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D004705:Endocytosis; D005786:Gene Expression Regulation; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D018448:Models, Immunological; D061251:Primary Cell Culture; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D019076:Transgenes
chemical_list: D000906:Antibodies; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen
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