Dysregulated T cell expression of TIM3 in multiple sclerosis

Area of Science:

• Immunology
• Neuroimmunology
• Cell Biology

Background:

• T cell immunoglobulin and mucin-domain containing molecule 3 (TIM3) is a T helper 1 (Th1)-associated molecule regulating Th1 responses and tolerance in mice.
• The expression and function of TIM3 in human T cells, particularly in the context of central nervous system autoimmunity like multiple sclerosis (MS), remain largely unknown.

Purpose of the Study:

• To investigate the expression and function of TIM3 in T cells from patients with multiple sclerosis (MS).
• To determine if TIM3 expression is altered in MS and if it contributes to disease pathogenesis.

Main Methods:

• Generation and analysis of 104 T cell clones from cerebrospinal fluid (CSF) of MS patients and control subjects.
• Assessment of cytokine profiles (e.g., interferon-gamma) and expression levels of TIM3 and T-bet.
• Interleukin 12-mediated polarization of T cell clones.
• Costimulatory blockade to induce tolerance.
• Small interfering (si)RNA-mediated reduction of TIM3 expression on ex vivo CD4+ T cells.

Main Results:

• MS CSF T cell clones exhibited higher interferon-gamma secretion but paradoxically lower TIM3 and T-bet expression compared to controls.
• Interleukin 12 stimulation led to increased interferon-gamma secretion and decreased TIM3 expression in MS clones relative to controls, indicating dysregulated TIM3 expression.
• Reduced TIM3 levels on MS CSF clones correlated with resistance to tolerance induction.
• TIM3 knockdown in human T cells enhanced proliferation and interferon-gamma secretion.

Conclusions:

• TIM3 expression is dysregulated in T cells from the cerebrospinal fluid of MS patients.
• Reduced TIM3 expression on human T cells enhances their proliferation and pro-inflammatory cytokine secretion.
• Failure to upregulate TIM3 in inflammatory sites may be an intrinsic defect contributing to the pathogenesis of MS and other autoimmune diseases.