TIM-3 and TIM-1 Could Regulate DecidualγδTCR Bright T Cells during Murine Pregnancy

Abstract

Pregnancy is an immunological enigma where paternal antigens are present at the fetomaternal interface. What regulates the local immunotolerance, which is necessary to prevent rejection of the conceptus, is still under strong investigation. Gamma/delta T cells are believed to play a role in the local regulation of this immunotolerance towards the semiallogenic fetus. Gamma/delta T cells from the uterus and spleen of pregnant and nonpregnant mice were analyzed by flow cytometry. We confirmed that the rate of γδT cells in the decidua increases during murine pregnancy and half of decidual γδT cells are CD4+. Furthermore, we found a unique association of CD4 or CD8 coreceptor expression with their γδTCR intensity, where in all investigated groups CD4- or CD8-positive γδT cells seemed principally to be γδTCRdim. In addition, compared to peripheral γδT lymphocytes, a greater proportion of decidual γδT cells expressed the cytotoxic marker CD107a and markers of Th1 or Th2 polarization (TIM-3, TIM-1), where decidual γδTCRbright cells were characterized by high TIM-3 and TIM-1 receptor expression. On the other hand, no difference in the expression of CD160, a receptor with dual function affecting cytotoxicity and T cell inhibition, was detected. Within lymphocytes expressing CD107a, TIM-1, or CD160, the rate of γδT cells was significantly higher in the decidua. According to our results, cytotoxic potential of decidual γδTCRbright cells could be regulated by TIM-3 ligation, while the TIM-1 receptor seems to be able to influence the Th1-Th2 balance at the fetomaternal interface. These mechanisms could play a part in the active maternal immunotolerance towards the fetus, allowing an efficient protection against pathogens during healthy murine pregnancy.

Gamma/Delta T Cells in the Course of Healthy Human Pregnancy: Cytotoxic Potential and the Tendency of CD8 Expression Make CD56+ γδT Cells a Unique Lymphocyte Subset

“…While abT cells are traditionally divided into CD4+ and CD8+ T cells, gdT cells are mainly classified based on their Vd-chainusage into circulating Vd2+ and resident Vd1+ cells. Although, there is a number of reports describing CD8 and/or CD4 positive gdT subtypes or clones (15,(48)(49)(50), gdT cells are mainly considered to be double negative and therefore these classical phenotype markers are rarely used in gdT cell research. According to our phenotypic characterization of peripheral blood gdT cells from pregnant and non-pregnant women, it is important to note that gdT cells can express CD4 and CD8.…”

“…We performed this well-established assay (42)(43)(44)(45) as described by Andzelm et al and previously presented in our publications (15,46,47): Cells were incubated for 4 h at 37°C and 5% CO 2 with the fluorochrome-conjugated anti-CD107a antibodies in RPMI 1640, supplemented with 10% FCS, penicillin, streptomycin, ionomycin (1 µg/ml) (Sigma-Aldrich) and phorbol myristate acetate (25 ng/ml) (Sigma-Aldrich). Before labeling with the other monoclonal antibodies the cells were washed and resuspended in RPMI 1640 with 5% FCS.…”

“…It can be assumed, that γδT cells have a regulatory function, which supports tolerance towards the semi-allogenic fetus on the one hand and intact defense against pathogens on the other ( 14 ). In our previous work we demonstrated the possible duality of γδT cell function in murine pregnancy: Decidual γδT cells have a strong cytotoxic potential, while expressing a tolerance promoting receptor profile ( 15 ).…”

Two functionally distinct subsets of IL‐17 producing γδ T cells

“…This difference in expression levels extends to the CD3 components of the TCR as well. 72,82,83 That they differ in this respect is intriguing because both the Vγ4 and Vγ6 + γδT-17 cells, as they reach the mature state in the thymus, become TCRhyporesponsive. Instead, they readily respond to certain cytokine mixtures, such as IL-1β plus IL-23, by producing IL-17 in the absence of any deliberate TCR stimulation.…”

A Brief Analysis of Tissue-Resident NK Cells in Pregnancy and Endometrial Diseases: The Importance of Pharmacologic Modulation

“…Another alternative that has not been explored in detail is single or multiple genetic polymorphisms of critical proteins, receptors, or signal transduction pathways that may be relevant for NK cell modulation and tissue migration [46]. Studies with the NK cell line NK-92 suggest that several exciting analyses could be performed using migration and invasion [66][67][68][69]. For example, STAT 3 was involved in Tim-3 dysregulation of dNK, which involves immune response against pathogen and tissue rejection [27,[67][68][69].…”