TIM-3: A Novel Regulatory Molecule of Alloimmune Activation

Abstract

T cell Ig domain and mucin domain (TIM)-3 has previously been established as a central regulator of Th1 responses and immune tolerance. In this study, we examined its functions in allograft rejection in a murine model of vascularized cardiac transplantation. TIM-3 was constitutively expressed on dendritic cells and natural regulatory T cells (Tregs) but only detected on CD4+FoxP3− and CD8+ T cells in acutely rejecting graft recipients. A blocking anti–TIM-3 mAb accelerated allograft rejection only in the presence of host CD4+ T cells. Accelerated rejection was accompanied by increased frequencies of alloreactive IFN-γ–, IL-6–, and IL-17–producing splenocytes, enhanced CD8+ cytotoxicity against alloantigen, increased alloantibody production, and a decline in peripheral and intragraft Treg/effector T cell ratio. Enhanced IL-6 production by CD4+ T cells after TIM-3 blockade plays a central role in acceleration of rejection. Using an established alloreactivity TCR transgenic model, blockade of TIM-3 increased allospecific effector T cells, enhanced Th1 and Th17 polarization, and resulted in a decreased frequency of overall number of allospecific Tregs. The latter is due to inhibition in induction of adaptive Tregs rather than prevention of expansion of allospecific natural Tregs. In vitro, targeting TIM-3 did not inhibit nTreg-mediated suppression of Th1 alloreactive cells but increased IL-17 production by effector T cells. In summary, TIM-3 is a key regulatory molecule of alloimmunity through its ability to broadly modulate CD4+ T cell differentiation, thus recalibrating the effector and regulatory arms of the alloimmune response.

Contrasting acute graft-versus-host disease effects of Tim-3/galectin-9 pathway blockade dependent upon the presence of donor regulatory T cells

“…Because Tregs can express gal-9, blockade of Tim-3/gal-9 binding may directly reduce the suppression of Tim-3 ϩ T-cells by gal-9 ϩ Tregs, thereby augmenting alloreactive Teff responses. 19,32 Contradictory to our expectations, inhibiting Tim-3/gal-9 binding using Tim-3 Ϫ/Ϫ donor T cells or Tim-3-Ig in the absence of donor Tregs did not augment but rather actually reduced GVHD lethality.The gut is the site of the largest immune compartment in the body and has a very complex immunologic environment. A significant amount of morbidity and mortality from GVHD is a consequence of damage to the gut leading to increased intestinal permeability.…”

“…Because Tregs can express gal-9, blockade of Tim-3/gal-9 binding may directly reduce the suppression of Tim-3 ϩ T-cells by gal-9 ϩ Tregs, thereby augmenting alloreactive Teff responses. 19,32 Contradictory to our expectations, inhibiting Tim-3/gal-9 binding using Tim-3 Ϫ/Ϫ donor T cells or Tim-3-Ig in the absence of donor Tregs did not augment but rather actually reduced GVHD lethality.…”

Perspectives for immunotherapy in endocrine cancer

“…TIM-3 is highly expressed on Tregs, monocytes, macrophages and DCs and is thought to confer reduced antitumor immunity (Zhou et al 2011). Inhibition of TIM-3 in naive CD4+ resulted in proliferation of CD8+ effector cells with increased CD8 T-cell cytotoxicity and increased TH1-mediated interferon-γ release (Sabatos et al 2003, Zhu et al 2005, Boenisch et al 2010. LAG3 is expressed on CD4, CD8 and activated Tregs (Huang et al 2004), B cells (Kisielow et al 2005) and a subset of NK cells (Baixeras et al 1992).…”

T cell immunoglobulin-3 as a new therapeutic target for rheumatoid arthritis

“…In addition, Tim-3 is involved in establishing tolerance. Although the precise mechanism of action by which Tim-3 establishes tolerance is not known, it is proposed that Tim-3 may regulate the graft-prolonging effects of anti-CD154/donor-specific transfusion by inducing the generation of donor-specific Tregs [18,20]. Collectively, in addition to inducing autoimmune diseases by regulating Th1 cell function, Tim-3 has also been implicated in establishing tolerance.…”

“…Tim-3 in the pathogenesis of RA Tim-3 is a Th1--associated cell surface protein that inhibits aggressive Th1-mediated autoimmune responses and promotes immune tolerance in mice [20,32].Tim-3 is also reported to promote or terminate Th1 immune responses and may influence a series of inflammatory conditions. The relative levels of expression of Tim-3 have previously been reported in peripheral blood mononuclear cells (PBMC) from patients with RA [33].…”