Maternal Krüppel-like factor 2 (KLF2)+ CD4 T cells promote fertility and fetal tolerance

Abstract

Pregnancy requires expanded maternal tolerance to semiallogeneic fetal-expressed antigens to protect against fetal loss and other pregnancy complications. Our understanding of how this biological imperative works remains uncertain. Here we show pregnancy primes expansion of antigen-experienced Krüppel-like factor 2 (KLF2)+ CD4 T cells with fetal specificity, and that these maternal cells play an essential role in optimal fertility and protecting against fetal resorption. Antigen-experienced KLF2+ CD4 cells purified from pregnant dams are poised for IL10 production and suppress responder T cell proliferation in coculture. Mice with conditional loss of KLF2 in T cells become pregnant less efficiently after allogeneic mating with genetically discordant males, but not after syngeneic mating with genetically identical males. Impaired fertility is associated with diminished and variable early pregnancy progesterone levels, whereas progression from mating to pregnancy is restored with exogenous progesterone. To bypass fertility defects, complementary experiments show that initiating induced KLF2 deletion in CD4 T cells midgestation causes fetal resorption associated with expansion of activated fetal-specific CD8 effector T cells across maternal tissues, particularly in the uterine draining lymph node and at the maternal–fetal interface. Reciprocally, these phenotypes are overturned with CD8 T cell depletion or in mice reconstituted with CD4 cells from wild-type donors which upregulate KLF2 expression in pregnant recipients. These findings demonstrate that maternal KLF2+ CD4 T cells promote fetal tolerance and fertility, particularly during allogeneic pregnancy.