Immunostimulatory Tim-1-specific antibody deprograms Tregs and prevents transplant tolerance in mice.
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.
Degauque
Nicolas
N
Division of Transplant Immunology and Transplant Research Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115, USA.
Mariat
Christophe
C
Kenny
James
J
Zhang
Dong
D
Gao
Wenda
W
Vu
Minh Diem
MD
Alexopoulos
Sophoclis
S
Oukka
Mohammed
M
Umetsu
Dale T
DT
DeKruyff
Rosemarie H
RH
Kuchroo
Vijay
V
Zheng
Xin Xiao
XX
Strom
Terry B
TB
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*
D000911:Antibodies, Monoclonal; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D020381:Interleukin-17; D008565:Membrane Proteins