Background: We have recently shown that 1/ activation of CD4 T cells via CD40 signaling plays a pivotal role in the early phase of liver ischemia/reperfusion injury (IRI); and 2/ disruption of "negative" TIM-3 – Gal-9 T cell costimulation exacerbates local inflammation response and dictates the severity of liver IRI in TLR4-dependent manner. We hypothesize that TIM-3 overexpressing T lymphocytes may modify innate immunity-driven hepatic IRI in vivo. Methods&Results: TIM-3 Tg mice were generated by expressing the full-length TIM-3 cDNA under the control of the human CD2 promoter on the C57BL/6 genetic background. In these mice, TIM-3 was highly expressed on peripheral CD4+ and CD8+ T lymphocytes (40-60% FACS confirmed positive). Groups (n=5/gr) of TIM-3 Tg and WT mice were subjected 90 min of partial warm partial hepatic ischemia, followed by 6 h reperfusion. TIM-3 Tg mice were protected against hepatic IRI, evidenced by sALT levels (1679±646 U/L vs. 8848±2262 U/L in controls, p<0.001). Unlike in WT counterparts, H/E stains showed well-preserved liver architecture in TIM-3 Tg hosts, with minimal sinusoidal congestion, without edema or vacuolization. The PD-1 levels were selectively up-regulated in TIM-3Tg IR-livers, implying that TIM-3 immunomodulation may preferentially promote the balance towards the "negative" T cell co-stimulation in vivo. Interestingly, TLR4 expression was significantly decreased in TIM-3 Tg IR-livers, compared with WT counterparts, which further indicates that TIM-3 negative regulation modulates macrophage-dependent hepatic innate immune activation/responses. In parallel, the expression of pro-inflammatory cytokines (TNF-Α, IL-1Β, and IFN-Β) and chemokine (CXCL10) was virtually abolished selectively in TIM-3 Tg IR-livers. Conclusion: Our novel findings support the crucial role of "adaptive" CD4 T cells in the mechanism of IR-liver "innate" inflammation response, and provide evidence that TIM-3 overexpressing T lymphocytes: 1) are defective in their ability to mount efficient immune responses; 2) fail to transmit pro-inflammatory signal to Kupffer cells/macrophages in IR-stressed livers; and 3) up-regulate negative PD-1 expression. Hence, harnessing physiological mechanisms of immune regulation by T cell-dependent TIM-3 promotes cytoprotection against innate immunity-induced organ damage. These results offer the rationale for refined new strategies to combat organ IRI in transplant recipients.

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