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

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.