title: Cutting edge: cell-extrinsic immune regulation by CTLA-4 expressed on conventional T cells.
abstract: The CTLA-4 pathway is a key regulator of T cell activation and a critical failsafe against autoimmunity. Although early models postulated that CTLA-4 transduced a negative signal, in vivo evidence suggests that CTLA-4 functions in a cell-extrinsic manner. That multiple cell-intrinsic mechanisms have been attributed to CTLA-4, yet its function in vivo appears to be cell-extrinsic, has been an ongoing paradox in the field. Although CTLA-4 expressed on conventional T cells (Tconv) can mediate inhibitory function, it is unclear why this fails to manifest as an intrinsic effect. In this study, we show that Tconv-expressed CTLA-4 can function in a cell-extrinsic manner in vivo. CTLA-4(+/+) T cells, from DO11/rag(-/-) mice that lack regulatory T cells, were able to regulate the response of CTLA-4(-/-) T cells in cotransfer experiments. This observation provides a potential resolution to the above paradox and suggests CTLA-4 function on both Tconv and regulatory T cells can be achieved through cell-extrinsic mechanisms.
authors: Medical Research Council Centre for Immune Regulation, University of Birmingham Medical School, Birmingham B15 2TT, United Kingdom.
authors: Chun Jing
authors: CJ
authors: Wang
authors: Rupert
authors: R
authors: Kenefeck
authors: Lukasz
authors: L
authors: Wardzinski
authors: Kesley
authors: K
authors: Attridge
authors: Claire
authors: C
authors: Manzotti
authors: Emily M
authors: EM
authors: Schmidt
authors: Omar S
authors: OS
authors: Qureshi
authors: David M
authors: DM
authors: Sansom
authors: Lucy S K
authors: LS
authors: Walker
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D060908:CTLA-4 Antigen / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006131:Growth Inhibitors / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007108:Immune Tolerance / Q000235:genetics; D007111:Immunity, Cellular / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011828:Radiation Chimera / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
chemical_list: D060908:CTLA-4 Antigen; D006131:Growth Inhibitors