Differential engagement of Tim-1 during activation can positively or negatively costimulate T cell expansion and effector function

Abstract

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-γ 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-γ 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.

T Cell Ig and Mucin Domain-1-Mediated T Cell Activation Requires Recruitment and Activation of Phosphoinositide 3-Kinase

“…However, anti-Tim-1 Abs targeting different epitopes of the Tim-1 extracellular domain have been shown to initiate either positive or negative effects on T cell activation (9,10,12). Thus, two anti-Tim-1 Abs, RMT1-10 and 3B3, differing by 17-fold in binding affinity to the same or closely related Tim-1 epitope in the IgV domain, exert opposite effects on T cell function (9). Although Tim-1 ligation by RMT1-10 apparently inhibits T cell activation, crosslinking with the higher affinity Ab 3B3 potentiates T cell activation.…”

Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells

“…Ligation of Tim-1 with its ligand Tim-4 in vitro induces T cell activation and proliferation (23). High-avidity binding of Tim-1 with an agonistic anti-Tim-1 antibody (3B3) induces production of proinflammatory cytokines IFN-␥ and IL-17 (14).…”

Anti‐TIM‐1 Monoclonal Antibody (RMT1‐10) Attenuates Atherosclerosis By Expanding IgM‐producing B1a Cells

“…TIM‐1 antibodies can be either an agonist or antagonist antibody that differentially modulate immune responses 17. Anti‐TIM‐1 antibody (Clone RMT1‐10) ameliorates Experimental autoimmune encephalomyelitis (EAE),17 allergic asthma,37 glomerulonephritis38 and corneal allograft rejection 39.…”

“…Anti‐TIM‐1 antibody (Clone RMT1‐10) ameliorates Experimental autoimmune encephalomyelitis (EAE),17 allergic asthma,37 glomerulonephritis38 and corneal allograft rejection 39. In contrast another anti‐TIM‐1 antibody (clone 3B3) enhances T cell proliferation and Th2 effector function 17, 40, 41. HFD‐fed LDLR‐deficient mice treated with anti‐TIM‐1 antibody (clone 3D10) accelerated atherosclerosis by ≈50% via increased aortic CD4 T cells 42.…”

“…In the prevention study, ApoE‐KO mice received either RMT1‐10 or IgG control intraperitoneally (0.2 mg/mouse)14, 17 on alternate days during an 8‐week HFD. In the intervention study,14, 17 ApoE‐KO mice fed an HFD for 6 weeks to establish atherosclerosis were treated with the same regimen of either RMT1‐10 or control IgG2a antibody while continuing an HFD for 8 weeks.…”