*Purpose: Carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1; CC1), a recently discovered ligand for T cell immunoglobulin domain and mucin domain-3 (TIM-3) on activated T cells, not only enhances TIM-3 expression but may also promote TIM-3-driven immune inhibitory functions. While TIM-3 has been explored as a therapeutic target to alleviate liver ischemia-reperfusion injury (IRI), whether CC1 on T cells can affect liver transplantation (LT) outcomes remains unknown. In the current study, we aimed to investigate the role of T cell-specific CC1 in mouse and human LT recipients.

*Methods: Wild type (WT) mouse livers were transplanted to groups of: WT, TIM-3 transgenic (TIM-3Tg), TIM-3Tg/CC1 knockout (CC1KO) double mutant, and CC1KO mouse. To evaluate the crosstalk between CC1 on T cells and TIM-3, CD4+ T cells isolated from these strains were adoptively transferred into Rag2 KO test recipients, followed by LT. In parallel, splenocytes isolated from the respective recipient strains were analyzed following T cell stimulation in vitro. Human liver graft biopsies (2h post-reperfusion) collected from 55 adult LT patients were assessed for immune activation markers.

*Results: Liver injury significantly deteriorated in CC1KO compared to WT recipients (AST: 7029±1105 vs 4100±484 U/L, p<0.05; ALT: 9356±1099 vs 5827±696 U/L, p<0.05; Suzuki's histological grading, p<0.01). Rag2 KO test mice reconstituted with purified CC1KO-T cells showed significantly enhanced liver damage compared to those reconstituted with WT-T cells (AST/ALT levels and Suzuki’s histological grading: p<0.05), indicating that CC1 on T cells mitigated posttransplant IRI. In addition, IRI in Rag 2 KO recipients reconstituted with TIM-3Tg/CC1KO-T cells was significantly augmented as compared with TIM-3Tg-T cells. This suggests that T cell-CC1 is required for TIM-3 regulation. In agreement with our in vivo findings, RT-PCR analysis for IL-2, IL-6, and interferon-γ revealed that splenocytes from TIM-3Tg/CC1KO double-mutant mice were highly susceptible to CD3 stimulation, while TIM-3-proficient T cells were immune suppressive. In the clinical arm, the expression of TIM-3 gene was significantly and negatively correlated with mRNA levels coding for TLR4, CD68, CD80, CD86, CXCL10, and cathepsin G in human OLT samples.

*Conclusions: This study identifies CC1 on T cells as a therapeutic target to alleviate LT injury via CC1/TIM-3 signaling.

« Back to 2022 American Transplant Congress