Differential engagement of Tim-1 during activation can positively or negatively costimulate T cell expansion and effector function.
It has been suggested that T cell immunoglobulin mucin (Tim)-1 expressed on T cells serves to positively costimulate T cell responses. However, crosslinking of Tim-1 by its ligand Tim-4 resulted in either activation or inhibition of T cell responses, thus raising the issue of whether Tim-1 can have a dual function as a costimulator. To resolve this issue, we tested a series of monoclonal antibodies specific for Tim-1 and identified two antibodies that showed opposite functional effects. One anti-Tim-1 antibody increased the frequency of antigen-specific T cells, the production of the proinflammatory cytokines IFN-gamma and IL-17, and the severity of experimental autoimmune encephalomyelitis. In contrast, another anti-Tim-1 antibody inhibited the generation of antigen-specific T cells, production of IFN-gamma and IL-17, and development of autoimmunity, and it caused a strong Th2 response. Both antibodies bound to closely related epitopes in the IgV domain of the Tim-1 molecule, but the activating antibody had an avidity for Tim-1 that was 17 times higher than the inhibitory antibody. Although both anti-Tim-1 antibodies induced CD3 capping, only the activating antibody caused strong cytoskeletal reorganization and motility. These data indicate that Tim-1 regulates T cell responses and that Tim-1 engagement can alter T cell function depending on the affinity/avidity with which it is engaged.
Xiao
Sheng
S
Center for Neurologic Diseases, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Najafian
Nader
N
Reddy
Jay
J
Albin
Monica
M
Zhu
Chen
C
Jensen
Eric
E
Imitola
Jaime
J
Korn
Thomas
T
Anderson
Ana C
AC
Zhang
Zheng
Z
Gutierrez
Cristina
C
Moll
Thomas
T
Sobel
Raymond A
RA
Umetsu
Dale T
DT
Yagita
Hideo
H
Akiba
Hisaya
H
Strom
Terry
T
Sayegh
Mohamed H
MH
DeKruyff
Rosemarie H
RH
Khoury
Samia J
SJ
Kuchroo
Vijay K
VK
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015551:Autoimmunity; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D004679:Encephalomyelitis / Q000276:immunology; D000072596:Hepatitis A Virus Cellular Receptor 1; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains; D011994:Recombinant Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology; D014162:Transfection
D000906:Antibodies; D017252:CD3 Complex; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D020381:Interleukin-17; D008565:Membrane Proteins; D011994:Recombinant Proteins; D007371:Interferon-gamma