Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance.
T helper type 1 (T(H)1) immune responses are central in cell-mediated immunity, and a T(H)1-specific cell surface molecule called Tim-3 (T cell immunoglobulin domain, mucin domain) has been identified. Here we report the identification of a secreted form of Tim-3 that contains only the immunoglobulin (Ig) variable (V) domain of the full-length molecule. Fusion proteins (Tim-3-Ig) of both Tim-3 isoforms specifically bound CD4(+) T cells, indicating that a Tim-3 ligand is expressed on CD4(+) T cells. Administration of Tim-3-Ig to immunized mice caused hyperproliferation of T(H)1 cells and T(H)1 cytokine release. Tim-3-Ig also abrogated tolerance induction in T(H)1 cells, and Tim-3-deficient mice were refractory to the induction of high-dose tolerance. These data indicate that interaction of Tim-3 with Tim-3 ligand may serve to inhibit effector T(H)1 cells during a normal immune response and may be crucial for the induction of peripheral tolerance.
Sabatos
Catherine A
CA
Department of Neurology, Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Chakravarti
Sumone
S
Cha
Eugene
E
Schubart
Anna
A
Sánchez-Fueyo
Alberto
A
Zheng
Xin Xiao
XX
Coyle
Anthony J
AJ
Strom
Terry B
TB
Freeman
Gordon J
GJ
Kuchroo
Vijay K
VK
D000906:Antibodies / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002455:Cell Division / Q000276:immunology / Q000502:physiology; D000072597:Hepatitis A Virus Cellular Receptor 2; D007107:Immune System / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology; D008024:Ligands; D020033:Protein Isoforms; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism*
D000906:Antibodies; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D008024:Ligands; D020033:Protein Isoforms; D011991:Receptors, Virus; D011993:Recombinant Fusion Proteins