Programmed cell death-1 (PD-1) and T-cell immunoglobulin mucin-3 (Tim-3) regulate CD4+ T cells to induce Type 2 helper T cell (Th2) bias at the maternal-fetal interface

STUDY QUESTION: Are the immune regulatory molecules programmed cell death-1 (PD-1) and T-cell immunoglobulin mucin-3 (Tim-3) involved in regulating CD4(+) T cell function during pregnancy? SUMMARY ANSWER: PD-1 and Tim-3 promote Type 2 helper T cell (Th2) bias and pregnancy maintenance by regulating CD4(+) T cell function at the maternal-fetal interface. WHAT IS KNOWN ALREADY: The maternal CD4(+) T cell response to fetal antigens is thought to be an important component of maternal-fetal tolerance during pregnancy. PD-1 and Tim-3 are important for limiting immunopathology. The co-expression of PD-1 and Tim-3 on T cells identifies a T cell subset with impaired proliferation and cytokine production. Combined blockade of Tim-3 and PD-1 could restore T cell function to the greatest degree. STUDY DESIGN, SIZE, DURATION: The expression of PD-1 and Tim-3 on CD4(+) Tcells was analyzed by flow cytometry, and in vitro and in vivo analyses were used to investigate the role of PD-1/Tim-3 signal in the regulation of CD4(+) T cells function and pregnancy outcome. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 88 normal pregnant women, 37 women with recurrent spontaneous abortion, 36 normal pregnant mice and 45 abortion-prone mice were included. We measure the expression of PD-1 and Tim-3 on CD4(+) T cells and their relationship to the function of CD4(+) T cells and pregnancy outcome, as well as the effects of blocking PD-1 and Tim-3 pathways on decidual CD4(+) T (dCD4(+)T) cells during early pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE: PD-1 and Tim-3, by virtue of their up-regulation on dCD4(+)T cells during pregnancy, define a specific effector/memory subset of CD4(+) T cells and promote Th2 bias at the maternal-fetal interface. Using in vitro and in vivo experiments, we also found that combined targeting of PD-1 and Tim-3 pathways results in decreased production of Th2-type cytokines by dCD4(+) T cells and increased fetal resorption of normal pregnant murine models. Moreover, decreased PD-1 and Tim-3 on dCD4(+) T cells may be associated with miscarriage. LIMITATIONS AND LIMITS OF CAUTION: Further study is required to examine the mechanism of PD-1 and Tim-3 effects on Th2 cytokine production by CD4(+) T cells during pregnancy. WIDER IMPLICATIONS OF THE FINDINGS: These results have important implications for understanding the physiological mechanisms that promote maternal-fetal tolerance. Our study also indicates that targeting Tim-3 and PD-1 pathways may represent novel therapeutic strategies to prevent pregnancy loss.