Feto-maternal immune regulation by TIM-3/galectin-9 pathway and PD-1 molecule in mice at day 14.5 of pregnancy

Abstract

a b s t r a c tIntroduction: Immunoregulation implies the activation of negative pathways leading to the modulation of specific immune responses. Co-inhibitory receptors (such as PD-1 and TIM-3) represent possible tools for this purpose. PD-1 and TIM-3 have been demonstrated to be present on immune cells suggesting general involvement in immunosuppression such as fetomaternal tolerance. The aim of our study was to investigate the expression pattern of PD-1, TIM-3, and its ligand Gal-9 on different immune cell subsets in the peripheral blood and at the fetomaternal interface in pregnant mice. Methods: TIM-3 and PD-1 expression by peripheral and decidual immune cells from pregnant BALB-c mice in 2 weeks of gestational age were measures by flow cytometry. Placental galectin-9 expression was determined by immunohistochemically and RT-PCR. Results: Gal-9 was found to be present in the spongiotrophoblast layer of the haemochorial placenta.Decidual NK, NKT and g/d T cells showed increased PD-1 expression and reduced cytotoxic potential when compared to the periphery. TIM-3 expression by NK cells and g/d T cells is similar both in the periphery and in the decidua, notably, their relative TIM-3 expression is increased locally which is associated with reduced lytic activity. Decidual NKT cells exhibit a reduced TIM-3 expression with increased relative receptor expression and a slightly increased cytotoxicity when compared to the periphery. Discussion: Our data reveals a particularly complex, tissue and cell type specific immunoregulatory mechanism by the investigated co-inhibitory receptors at the fetomaternal interface.

PD-L1 Expression in Premalignant and Malignant Trophoblasts From Gestational Trophoblastic Diseases Is Ubiquitous and Independent of Clinical Outcomes

“…Other immune cells might also be involved in trophoblast tolerance, because PD-1 expression is increased in dNK cells from pregnant mice. 18 This present study also shows an intense peritumoral immune infiltration of almost all types of GTN. Interestingly, the nature of these immune infiltrates was previously investigated.…”

“…It is assumed that PD-L1 expression on trophoblasts prevents the T H 17 differentiation of paternal alloantigen-specific T helper cells. Trophoblast PD-L1 may also directly interact with dNK cells 18 and inhibit their cytotoxic effect. Interestingly, PD-1 blockade in blood cells from patients with melanoma and prostate cancer induced a switch from T H 2 to T H 1/T H 17 response with higher levels of interferon F, IL-2, IL-6, and IL-17.…”

The immune dysfunction in ankylosing spondylitis patients

“…T-cell immunoglobulin and mucin-domain-containing molecule 3 (Tim-3), often expressed in Th1, Th17, and CD8 + T cells (17), has been known to downregulate immune responses and control inflammation (18). PD-1 and Tim-3 are often found to have unusual expression in chronic infections and autoimmune diseases, including HIV infection (19), tuberculosis (19), sepsis (20), and feto-maternal immune regulation (21).…”

Expression of inhibitory receptors and polyfunctional responses of T cells are linked to the risk of congenital transmission of T. cruzi

“…Thus, in pregnancy, the immune system has the duties of defending the mother and the fetus from foreign pathogens while simultaneously tolerating the paternal alloantigens expressed by the fetus [26]. The regulation of the immune effector functions is mediated by cellular and molecular interactions with numerous cellular components of the immune system and also by a vast amount of molecules with immunoregulatory capacities, such as inhibitory receptors [10]. However, although these immune mechanisms are needed for fetal protection, they can be a risk factor for the congenital transmission of infectious diseases.…”

“…This immune homeostasis is mediated by cellular and molecular mechanisms that include the immunosuppressive effects of regulatory T cells and the immunoregulatory capacity of molecules that are involved in the inhibition of specific immune responses [9, 10]. This natural process of immunosuppression in pregnant women infected with T .…”