T Cell Ig- and Mucin-Domain-Containing Molecule-3 (TIM-3) and TIM-1 Molecules Are Differentially Expressed on Human Th1 and Th2 Cells and in Cerebrospinal Fluid-Derived Mononuclear Cells in Multiple Sclerosis

Abstract

T cell Ig- and mucin-domain-containing molecules (TIMs) comprise a recently described family of molecules expressed on T cells. TIM-3 has been shown to be expressed on murine Th1 cell clones and has been implicated in the pathogenesis of Th1-driven experimental autoimmune encephalomyelitis. In contrast, association of TIM-1 polymorphisms to Th2-related airway hyperreactivity has been suggested in mice. The TIM molecules have not been investigated in human Th1- or Th2-mediated diseases. Using real-time (TaqMan) RT-PCR, we show that human Th1 lines expressed higher TIM-3 mRNA levels, while Th2 lines demonstrated a higher expression of TIM-1. Analysis of cerebrospinal fluid mononuclear cells obtained from patients with multiple sclerosis revealed significantly higher mRNA expression of TIM-1 compared with controls. Moreover, higher TIM-1 expression was associated with clinical remissions and low expression of IFN-γ mRNA in cerebrospinal fluid mononuclear cells. In contrast, expression of TIM-3 correlated well with high expression of IFN-γ and TNF-α. These data imply the differential expression of human TIM molecules by Th1 and Th2 cells and may suggest their differential involvement in different phases of a human autoimmune disease.

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

“…In the mouse system, we favor the hypothesis that TIM-1 functions to preferentially enhance the activity or survival of Th2 T cells after their initial differentiation has taken place (29). This model is consistent with the observation that TIM-1 is highly induced on mouse and human T cells after several rounds of Th2 differentiation in vitro (11,19). The data are also consistent with the pattern of cytokine expression induced in human primary T cells upon TIM-1 transfection, as both Th1 and Th2 cytokines were expressed, suggesting that TIM-1-mediated activation amplified the existing T cell response, rather than causing skewing to a strictly Th2 state (Fig.…”

“…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).…”

Attenuation of Th1 response through galectin‐9 and T‐cell Ig mucin 3 interaction inhibits autoimmune diabetes in NOD mice

“…TIM-3 expression has been reported on mouse Th17 cells [34], DC, monocytes, macrophages [35] and on human NK and NK-T cells [36], indicating that TIM-3 may have different functions in adaptive and innate immunity. Interestingly, the gal-9-TIM-3 pathway showed a stimulatory function in DC, with an enhanced inflammatory response by TIM-3-expressing DC during the innate immune response [37].…”

Blockade of Tim-3 Pathway Ameliorates Interferon-γ Production from Hepatic CD8+ T Cells in a Mouse Model of Hepatitis B Virus Infection

“…The administration of anti-Tim-3 mAbs augmented the activation of effector T cells expressing IFN-. So far, evidence has been provided for an important role of Tim-3 in a range of diseases, including inflammatory diseases (14)(15)(16)(17)(18)(19). However, no study has been reported on the role of Tim-3 in immune repression during HBV infection.…”