TIM-3 ameliorates host responses to Salmonella infection by controlling iron driven CD4+ T cell differentiation and interleukin-10 formation.

Background: Iron loading increases infection risk in being a nutrient for invading siderophilic bacteria and by modulating immune functions including the expression of the immune checkpoint regulator T-cell immunoglobulin-and-mucin-containing-domain-3 (TIM-3). TIM-3 affects specific immune cell functions including T-helper cell differentiation but also T cell dysfunction, and immune exhaustion. Given the prevalence of iron overload specifically in patients at higher risk for infection such as those suffering from hemo-oncological diseases, we investigated TIM-3's role in immune control of bacterial sepsis.

Methods: A sepsis model was employed in wildtype and Tim3^-/- mice with transgenic expression of a functional natural resistance associated macrophage protein 1 (NRAMP1). This creates a chronic inflammation model with enhanced resistance to infections with Gram negative Salmonella typhimurium, enabling to study T cell immune responses over time.

Findings: Dietary iron supplementation reduced mouse survival, which was further exaggerated by TIM-3 deletion. This indicates that TIM-3 dependent immune regulation was essential for effective host defence against Salmonella. TIM-3 deletion increased the production of immune-deactivating interleukin (IL) -10 as a result of impaired interleukin-12 receptor (IL-12R)-dependent CD4⁺ cytotoxic T cell signalling and development which subsequently reduced the production of anti-microbial interferon gamma (IFNγ). Anti-IL-10 treatment in iron-loaded Tim3^-/- mice improved Salmonella control and restored CD4⁺ T cell mediated IFNγ production.

Interpretation: Our study uncovers TIM-3 as a crucial regulator of T cell driven immune control of bacterial infection and identifies the underlying treatable pathways, which is of major importance to better combat infection related mortality in subjects with iron overload syndromes.

Funding: Christian-Doppler-Society, FWF (I-3321, W-1253).