*Purpose: Cirrhosis-related immune dysfunction likely contributes to early mortality following liver transplant (LT) resulting from infections. We previously identified a pre-transplant biomarker panel for immune dysfunction – the immune frailty index (IFI). IFI predicts early mortality following LT; however, the mechanism is unknown. Here, we evaluate alterations in recipient CD4⁺ T cell repertoire and T cell exhaustion as potential causes for immune frailty in LT recipients.

*Methods: Prior analysis demonstrated that HCV viral load, pre-LT plasma Eotaxin, MMP3, and Fractalkine predict 1yr mortality. An immune frailty index (IFI) was created by assigning 1 point for each factor above the median. High IFI pts were matched 1:2 with low IFI pts and healthy controls (HC) based on age, gender, and cause of liver disease. Multiparametric flow cytometric analysis was performed.

*Results: Pts with a low IFI (Score 0-2, N=112) have 95.5% 1yr survival compared with 46.2% for high IFI (Score 3-4, N=13). Cause of death was most commonly sepsis in high IFI; whereas cardiac mortality was more common in low IFI. To augment variability between pts, high IFI (N=4) were matched 1:2 with low IFI (N=7) based on gender, age and cause of liver disease. Demographics were equivalent between groups, except for a trend towards lower Karnofsky score in high IFI (p=0.12). Similar to the larger cohort, matched high IFI more likely developed infections (50% vs 0%, p=0.05). Survival was 50% & 25% at 1- and 2-yrs for IFI high versus 100% at 1- and 2-yrs for IFI low (p=0.02). Both groups exhibit significant decrease in naïve and effector CD4 cells and increase in central memory, effector memory, and regulatory CD4⁺ T cells compared to HC (p<0.01), but subsets were similar between IFI high and low. Exhausted CD4⁺ T cell subsets (PD-1⁺) were more also more frequent in both groups compared with HC, but IFI high demonstrated a significant increase in CD4⁺ T cell exhaustion amongst central memory (p=0.02) and effector memory CD4⁺ T cells (p=0.04).

*Conclusions: We have identified pre-transplant Eotaxin, Fractalkine, and MMP3 as potential biomarkers to predict post-transplant mortality. The resulting IFI has potential to identify pts at increased risk for futile outcomes prior to LT and augment clinical assessment among high acuity recipients. Increase in CD4 T cell exhaustion in pts at high risk of immune frailty may contribute to vulnerability of such recipients to infections and other immune related events following LT.

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