Cytotoxic potential of decidual NK cells and CD8+ T cells awakened by infections

Abstract

To establish a healthy pregnancy the maternal immune system must tolerate fetal allo-antigens, yet remain competent to respond to infections. The ability of decidual NK cells (dNK) to promote migration of fetal extravillous trophoblasts (EVT) and placental growth as well as the capacity of EVT to promote immune tolerance are topics of high interest and extensive research. However, the problem of how dNK and decidual CD8+ T cells (CD8+ dT) provide immunity to infections of the placenta and the mechanisms that regulate their cytolytic function has thus far largely been ignored. Fetal EVT are the most invasive cells of the placenta and directly interact with maternal decidual immune cells at this maternal-fetal interface. Besides the expression of non-polymorphic HLA-E and HLA-G molecules that are associated with immune tolerance, EVT also express highly polymorphic HLA-C molecules that can serve as targets for maternal dNK and CD8+ dT responses. HLA-C expression by EVT has a dual role as the main molecule to which immune tolerance needs to be established and as the only molecule that can present pathogen-derived peptides and provide protective immunity when EVT are infected. The focus of this review is to address the regulation of cytotoxicity of dNK and CD8+ dT, which is essential for maternal-fetal immune tolerance as well as recent evidence that both cell types can provide immunity to infections at the maternal-fetal interface. A particular emphasis is given to the role of HLA-C expressed by EVT and its capacity to elicit dNK and CD8+ dT responses.

An immunogenic phenotype in paternal antigen‐specific CD8+ T cells at embryo implantation elicits later fetal loss in mice

“…In healthy pregnancy, these cells have a CD103 + regulatory phenotype with a proportion of cells expressing FOXP3, and absence of CD28 and the cytolytic protein perforin 47 . However, upon pro‐inflammatory cytokine stimulation and with TCR ligation mimicking infection, they can become cytolytic 48 …”

“…47 However, upon pro-inflammatory cytokine stimulation and with TCR ligation mimicking infection, they can become cytolytic. 48 TGFB and IL10 are known to dictate the fate of T cells through effects on antigen presenting cells. IL10 drives macrophages in the uterine decidua into an immunoregulatory phenotype, with low expression of TNF, IL6, IL1A, IL8, IL12 and costimulatory molecules, and suppress capacity to elicit a Th1 response.…”

An altered endometrial CD8 tissue resident memory T cell population in recurrent miscarriage

“…Similar to murine studies, CD69 and CD103 are highly expressed by mucosal human memory CD8-T cells, in contrast to circulating memory CD8-T cells31415. While studies have investigated memory T cells in the decidua (the modified endometrium during pregnancy) using tissues obtained from elective abortions or term pregnancies1617, a detailed analysis of residency markers on CD8-T memory cells in non-pregnant endometrium, has not yet been performed. Here we isolate and phenotype endometrial CD8-T cells in the mid-luteal phase of the menstrual cycle (the time relevant for embryo implantation) and demonstrate that these cells are altered in women who have experienced recurrent miscarriage (RM), a condition hypothesised to have an immune mediated mechanism.…”

Future prospects for CD8+ regulatory T cells in immune tolerance

“…39 Other more classical cytokines such as TGFβ have also been described as playing a role in CD8 + Treg suppressive activity. 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. 40,41 Indeed, in maternal tolerance where the allogeneic fetal trophoblast invades maternal tissues and interacts with maternal leukocytes, the immune system needs to be regulated to tolerate the presence of the fetus.…”

“…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. Particularly in mice and humans, the best described population of mouse CD8αα + TCRαβ + Tregs or human CD8 + Tregs (no specific phenotype associated except pMHC restriction) has been described to preferentially recognize non-classical MHC class I molecules Qa-1 or HLA-E that are orthologous genes.…”