Inflammation: TIM3: dual role in immunity

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In addition to its known role as a negative regulator of T helper 1 (T_H1)-cell responses, TIM3 (T-cell immunoglobulin domain and mucin domain 3) can promote pro-inflammatory responses by affecting the production of tumor-necrosis factor (TNF) and inducing the expression of nuclear factor- kappa B (NF- kappa B) in dendtiric cells.

Previous studies have identified TIM3 (T-cell immunoglobulin domain and mucin domain 3) as a negative regulator of T helper 1 (T_H1)-cell responses. Now, new research shows that TIM3 is also expressed by innate immune cells and can promote a pro-inflammatory response, indicating that TIM3 has a dual role in immunity.

TIM3 is activated by galectin-9, is expressed by T_H1 cells and suppresses aggressive T_H1-cell responses. In this study, Anderson et al. showed that TIM3 is also expressed by naive dendritic cells (DCs) and monocytes in both mice and humans. Unexpectedly, they found that TIM3 can synergize with lipopolysaccharide in the production of the pro-inflammatory cytokine tumour-necrosis factor (TNF) and that it directly induces the expression of nuclear factor- kappa B (NF- kappa B) in DCs.

Multiple sclerosis is a disease of the central nervous system (CNS) that is associated with the pro-inflammatory cytokines interferon- gamma and TNF. Interestingly, the authors showed that microglia and infiltrating monocytes isolated from the active border of lesions in the CNS of patients with multiple sclerosis expressed higher levels of TIM3 than cells isolated from non-inflamed CNS tissues or from patients with glioblastoma multiforme tumours (a CNS disorder that does not have a pro-inflammatory cytokine profile). In addition, the expression of galectin-9 by human astrocytes is upregulated in inflamed multiple sclerosis lesions. In a mouse model of multiple sclerosis, the expression of TIM3 by microglia and CNS monocytes was at its highest just before the peak of clinical manifestation of the disease, and the severity of disease was greater in mice that received a TIM3 agonist in the immunization protocol compared with those that did not. So, TIM3 can promote inflammation through its expression by innate immune cells.

But how can one molecule have two different effects on an inflammatory response? The authors showed that a different pattern of tyrosine phosphorylation was induced in DCs compared with T cells early after TIM3 engagement, but the exact identity of the proteins that were phosphorylated is not yet known. It is possible that this difference in the proximal signalling pathways induced by TIM3 may account for the difference in its effect on innate and adaptive immune cells.

So, depending on which cell type it is expressed by, TIM3 can promote inflammation or restrain T_H1-cell responses. Further studies on TIM3 could help us to understand how the balance between the promotion and inhibition of tissue inflammation is regulated.

Olive Leavy

References

Anderson, A. C. et al. Promotion of tissue inflammation by the immune receptor Tim-3 expressed on innate immune cells. Science 318, 1141–1143 (2007) | Article | PubMed |