Dysfunctional Decidual CD4+T Cells Induce Recurrent Pregnancy Loss via Palmitoylation‐Dependent Tim‐3 Lysosomal Sorting and Degradation

Abstract Palmitoylation is a fully reversible post‐translational modification that regulates the functions of various proteins. While its dysregulation has been implicated in numerous pathological processes, there has been scarce researches on palmitoylation changes in proteins associated with recurrent pregnancy loss (RPL). Utilizing palmitoylation proteomics, 3262 proteins are identified with increased palmitoylation and 1577 proteins with decreased palmitoylation in the decidual immune cells from RPL patients compared to those from normal early pregnancies. Reduced palmitoylation by 2‐bromopalmitate promoted decidual CD4 + T (dCD4 + T) cell tolerance and decrease the resorption rate of abortion‐prone mice, suggesting that elevated palmitoylation level may be associated with RPL. The bioinformatics, proteomic, functional and mouse model studies revealed that T cell immunoglobulin domain and mucin domain‐3 (Tim‐3) is palmitoylated by ZDHHC3 on cysteine 9 residue. This palmitoylated‐Tim‐3 subsequently bound to sortilin and was directed to lysosome for degradation, leading to decreased expression of Tim‐3 and the dysfunction of dCD4 + T cells, ultimately resulting in fetal loss. We elucidated a pivotal role for dynamic palmitoylation in RPL and uncovered a novel mechanism governing Tim‐3 regulation. Given that Tim‐3 dysregulation is frequently linked to RPL, our findings may have important implications for understanding the etiology of RPL and developing targeted therapy of RPL.