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Maternal decidual CD8 +  T (dCD8 +  T) cells must integrate the antithetical demands of maternal–fetal tolerance and anti-viral immunity to establish a successful pregnancy. T-cell immunoglobulin mucin-3 (Tim-3) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are two important co-inhibitory molecules that regulating CD8 +  T cells responses during infection and tumor. In the present study, we examined the co-expression of Tim-3 and CTLA-4 on CD8 +  T cells during pregnancy and found the higher frequency of Tim-3 + CTLA-4 + dCD8 +  T cells in response to trophoblasts. This Tim-3 + CTLA-4 + dCD8 +  T cells subset showed an active status and produced more anti-inflammatory cytokines. Furthermore, the decreased number and altered function of Tim-3 + CTLA-4 + dCD8 +  T cells correlated to miscarriage. Combined blocking Tim-3 and CTLA-4 pathways were highly effective in inhibiting the production of anti-inflammatory cytokines and were detrimental to the maintenance of pregnancy. Together, these findings supported that Tim-3 and CTLA-4 pathways might play positive roles in the establishment and/or maintenance of maternal–fetal tolerance so to promote the maintenance of normal pregnancy. So the reproductive safety must be considered, especially when anti-Tim-3/CTLA-4 antibody (and other immune checkpoint inhibitors) are used in pregnancy.

The appropriate frequency and function of decidual Tim-3+CTLA-4+CD8+ T cells are important in maintaining normal pregnancy