title: Immunostimulatory Tim-1-specific antibody deprograms Tregs and prevents transplant tolerance in mice.
abstract: T cell Ig mucin (Tim) molecules modulate CD4(+) T cell responses. In keeping with the view that Tim-1 generates a stimulatory signal for CD4(+) T cell activation, we hypothesized that an agonist Tim-1-specific mAb would intensify the CD4(+) T cell-dependant allograft response. Unexpectedly, we determined that a particular Tim-1-specific mAb exerted reciprocal effects upon the commitment of alloactivated T cells to regulatory and effector phenotypes. Commitment to the Th1 and Th17 phenotypes was fostered, whereas commitment to the Treg phenotype was hindered. Moreover, ligation of Tim-1 in vitro effectively deprogrammed Tregs and thus produced Tregs unable to control T cell responses. Overall, the effects of the agonist Tim-1-specific mAb on the allograft response stemmed from enhanced expansion and survival of T effector cells; a capacity to deprogram natural Tregs; and inhibition of the conversion of naive CD4(+) T cells into Tregs. The reciprocal effects of agonist Tim-1-specific mAbs upon effector T cells and Tregs serve to prevent allogeneic transplant tolerance.
authors: Division of Transplant Immunology and Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors: Nicolas
authors: N
authors: Degauque
authors: Christophe
authors: C
authors: Mariat
authors: James
authors: J
authors: Kenny
authors: Dong
authors: D
authors: Zhang
authors: Wenda
authors: W
authors: Gao
authors: Minh Diem
authors: MD
authors: Vu
authors: Sophoclis
authors: S
authors: Alexopoulos
authors: Mohammed
authors: M
authors: Oukka
authors: Dale T
authors: DT
authors: Umetsu
authors: Rosemarie H
authors: RH
authors: DeKruyff
authors: Vijay
authors: V
authors: Kuchroo
authors: Xin Xiao
authors: XX
authors: Zheng
authors: Terry B
authors: TB
authors: Strom
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D000072596:Hepatitis A Virus Cellular Receptor 1; D020381:Interleukin-17 / Q000378:metabolism; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D051379:Mice; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology; D023001:Transplantation Tolerance / Q000187:drug effects* / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D020381:Interleukin-17; D008565:Membrane Proteins