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

Abstract

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 Role of B7 Family Molecules in Maternal–Fetal Immunity

“…B7-1 and B7-2 bind to CTLA-4 with greater affinity than CD28, and therefore, CTLA-4 might play a particular role in the mediation of maternal-fetal immunity (29). Previous studies have proven that the appropriate frequency and function of decidual Tim-3 + CTLA-4 + CD8 + T cells are important in the maintenance of normal human pregnancy (30). Along with its constitutive and restricted expression on Tregs, CTLA-4 expression is involved in the immune-suppressive function of these cells (31).…”

Future prospects for CD8+ regulatory T cells in immune tolerance

“…This was the first description of a role for this cytokine in T cell biology and transplantation. [42][43][44] Decreased number and altered function of Tim-3 + CTLA-4 + CD8 + T cells correlated with miscarriage and blockade of Tim-3 and CTLA-4 inhibited production of anti-inflammatory cytokines and were detrimental in the maintenance of the pregnancy. 39 Other more classical cytokines such as TGFβ have also been described as playing a role in CD8 + Treg suppressive activity.…”

“…38 Thus, a complex regulatory network of cells around CD8 + Tregs is acting to sustain tolerance. 42 Allogeneic fetal trophoblasts express the non-classical major histocompatibility complex (MHC) class I molecule human leukocyte antigen G which is needed for immune tolerance establishment and was shown to increase the number of Tregs. 2 Some of these molecules or mechanisms of action have been evidenced by study of the fetal-maternal interface.…”

“…CD8 + T cells are the main component of decidual T cells and CD8 + Tregs have been evidenced as important in the maintenance of a normal pregnancy. [42][43][44] Decreased number and altered function of Tim-3 + CTLA-4 + CD8 + T cells correlated with miscarriage and blockade of Tim-3 and CTLA-4 inhibited production of anti-inflammatory cytokines and were detrimental in the maintenance of the pregnancy. 42 Allogeneic fetal trophoblasts express the non-classical major histocompatibility complex (MHC) class I molecule human leukocyte antigen G which is needed for immune tolerance establishment and was shown to increase the number of Tregs.…”

“…[42][43][44] Decreased number and altered function of Tim-3 + CTLA-4 + CD8 + T cells correlated with miscarriage and blockade of Tim-3 and CTLA-4 inhibited production of anti-inflammatory cytokines and were detrimental in the maintenance of the pregnancy. 42 Allogeneic fetal trophoblasts express the non-classical major histocompatibility complex (MHC) class I molecule human leukocyte antigen G which is needed for immune tolerance establishment and was shown to increase the number of Tregs. 45,46 MHC restriction preference of CD8 + Tregs has been shown as important for their suppressive activity and for some subpopulations of CD8 + Tregs different from what has been described for CD8 + Teff cells.…”