TIM-1 induces T cell activation and inhibits the development of peripheral tolerance

Umetsu, Sarah E.; Lee, Wan-Ling; McIntire, Jennifer J.; Downey, Laura; Sanjanwala, Bharati; Akbari, Omid; Berry, Gerald J.; Nagumo, Haruo; Freeman, Gordon J.; Umetsu, Dale T.; DeKruyff, Rosemarie H.

doi:10.1038/ni1186

Cited by 287 publications

(350 citation statements)

References 26 publications

Supporting

Mentioning

326

Contrasting

Unclassified

Order By: Relevance

“…Tim-3 has been proposed to be a novel candidate target for the treatment of SLE. [32][33][34][35][36][37] Unlike the other Tim molecules, Tim-4 is exclusively expressed in APCs and it is unclear to date whether Tim-4 plays a role in SLE pathogenesis. Due to the lack of a directly labeled anti-human Tim-4 antibody, it is difficult to quantitate Tim-4 protein on APCs by flow cytometry.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of human T-cell immunoglobulin- and mucin-domain-containing molecule-4 in peripheral blood mononuclear cells from patients with system lupus erythematosus

Zhao

Wang³

et al. 2010

Cell Mol Immunol

View full text Add to dashboard Cite

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease. Innate and adaptive immunity cooperatively contribute to the development of SLE. Antigen-presenting cells (APCs) have been suggested to link innate and adaptive immunity. T-cell immunoglobulin-and mucin-domain-containing molecule-4 (Tim-4; also known as Timd4), expressed primarily on the surface of APCs, is a member of the TIM family, a recently described group of molecules that have received much attention as potential regulators of the immune system. In this study, we used quantitative real-time reverse transcription-polymerase chain reaction to examine the mRNA expression of Tim-4 in peripheral blood mononuclear cells (PBMCs) from SLE patients and further analyzed the correlation between the expression of Tim-4 and Tim-1 (a potential ligand for Tim-4) in PBMCs and serum tumor necrosis factor (TNF)-a levels. The results showed that Tim-4 mRNA expression in PBMCs was significantly higher in SLE patients than in healthy controls, especially those patients in the active phase of disease. Moreover, Tim-4 mRNA levels were closely correlated with Tim-1 mRNA levels in PBMCs and with serum TNF-a levels in SLE patients but not in the control group. Taken together, these results demonstrate that Tim-4 may be involved in the pathogenesis of SLE.

show abstract

Section: Discussionmentioning

confidence: 99%

Increased expression of human T-cell immunoglobulin- and mucin-domain-containing molecule-4 in peripheral blood mononuclear cells from patients with system lupus erythematosus

Zhao

Wang³

et al. 2010

Cell Mol Immunol

View full text Add to dashboard Cite

show abstract

“…It has been established that TIM-1 mRNA and protein are expressed in both mouse (1,11,18) and human (14,19) CD4 ϩ T cells following activation. To study the downstream signaling effects of TIM-1 expression in human T cells, multiple immortalized lines from ATCC and elsewhere were tested for TIM-1 expression by FACS analysis, but no TIM-1-positive cell lines were found (data not shown).…”

Section: Tim-1 Overexpression Induces T Cell Activation Signalsmentioning

confidence: 99%

“…For example, studies of TIM-1 responses induced by an anti-murine TIM-1 mAb or by murine TIM-4, a putative TIM-1 ligand, showed that engagement of TIM-1 up-regulated cellular proliferation and the expression of Th1 and Th2 cytokines both in vitro and in vivo (11,12). However, administration of the TIM-1-Fc fusion protein to mice also upregulated immune responses (12), a result seemingly at odds with the proposed model of TIM-1 action.…”

mentioning

confidence: 99%

Human TIM-1 Associates with the TCR Complex and Up-Regulates T Cell Activation Signals

Binné

Scott

Rennert

2007

The Journal of Immunology

View full text Add to dashboard Cite

The T cell, Ig domain, and mucin domain-1 (TIM-1) gene is associated with Th2 T cell responses and human atopic diseases. The mechanism by which TIM-1 influences T cell responses remains unknown. We demonstrate that TIM-1 is recruited to the TCR-signaling complex via association with CD3. TIM-1 up-regulates TCR-associated signaling events, including phosphorylation of Zap70 and IL-2-inducible T cell kinase. This activity requires TIM-1 tyrosine phosphorylation. TIM-1 expression induces formation of a novel complex that includes PI3K and ITK. Finally, the consequences of TIM-1 activation include increased expression of effector cytokines. These results demonstrate that TIM-1 is a critical component of the human T cell response and provide a mechanistic hypothesis for the role of TIM-1 in disease.

show abstract

“…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.…”

Section: Discussionmentioning

confidence: 99%

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

Hosseini

Kanellakis

et al. 2018

JAHA

View full text Add to dashboard Cite

BackgroundPeritoneal B1a cells attenuate atherosclerosis by secreting natural polyclonal immunoglobulin M (IgM). Regulatory B cells expressing T‐cell immunoglobulin mucin domain‐1 (TIM‐1) expanded through TIM‐1 ligation by anti‐TIM‐1 monoclonal antibody (RMT1‐10) induces immune tolerance.Methods and ResultsWe examined the capacity of RMT1‐10 to expand peritoneal B1a cells to prevent atherosclerosis development and retard progression of established atherosclerosis. RMT1‐10 treatment selectively doubled peritoneal B1a cells, tripled TIM‐1+ B1a cells and increased TIM‐1+IgM+interleukin (IL)‐10+ by 3‐fold and TIM‐1+IgM+IL‐10− B1a cells by 2.5‐fold. Similar expansion of B1a B cells was observed in spleens. These effects reduced atherosclerotic lesion size, increased plasma IgM and lesion IgM deposits, and decreased oxidatively modified low‐density lipoproteins in lesions. Lesion CD4+ and CD8+ T cells, macrophages and monocyte chemoattractant protein‐1, vascular cell adhesion molecule‐1, expression of proinflammatory cytokines monocyte chemoattractant protein‐1, vascular cell adhesion molecule‐1, IL1β, apoptotic cell numbers and necrotic cores were also reduced. RMT1‐10 treatment failed to expand peritoneal B1a cells and reduce atherosclerosis after splenectomy that reduces B1a cells, indicating that these effects are B1a cell‐dependent. Apolipoprotein E‐KO mice fed a high‐fat diet for 6 weeks before treatment with RMT1‐10 also increased TIM‐1+IgM+ IL‐10+ and TIM‐1+IgM+ IL‐10− B1a cells and IgM levels and attenuated progression of established atherosclerosis.Conclusions RMT1‐10 treatment attenuates atherosclerosis development and progression by selectively expanding IgM producing atheroprotective B1a cells. Antibody‐based in vivo expansion of B1a cells could be an attractive approach for treating atherosclerosis.

show abstract

TIM-1 induces T cell activation and inhibits the development of peripheral tolerance

Cited by 287 publications

References 26 publications

Increased expression of human T-cell immunoglobulin- and mucin-domain-containing molecule-4 in peripheral blood mononuclear cells from patients with system lupus erythematosus

Increased expression of human T-cell immunoglobulin- and mucin-domain-containing molecule-4 in peripheral blood mononuclear cells from patients with system lupus erythematosus

Human TIM-1 Associates with the TCR Complex and Up-Regulates T Cell Activation Signals

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

Contact Info

Product

Resources

About