ROLE OF CYTOXIC T-LYMPHOCYTES IN THE PATHOGENESIS OF PRETERM BIRTH

Currently, the existence of a wide range of subpopulations of CD8⁺T-lymphocytes has been revealed, among which there are subpopulations of naive and effector cells, as well as memory cells. CD8⁺T-lymphocytes are thought to be a population of lymphocytes with high cytotoxic activity, which is of extreme importance during pregnancy. Given that each subpopulation is characterized by a set of produced mediators, surface and intracellular markers, we can assume their role in the pathogenesis of preterm birth. This determined the need to investigate the role of naive cells, effector cells, and memory cells in the development of spontaneous preterm birth. Data on the content of naive CD8⁺-lymphocytes in the peripheral blood of women with threatened preterm birth are practically absent. It was found that the infiltration of CD8⁺-lymphocytes in the area of uteroplacental contact was associated with the development of timely delivery. Chronic chorioamnionitis is the most common condition in idiopathic preterm birth and is characterized by the infiltration of maternal CD8⁺Tcells into the chorioamniotic membranes. Currently, it is believed that chronic inflammatory lesions of the placenta represent maternal antifetal rejection. This led to the study of the role of these cells in the pathogenesis of preterm birth. Purpose. To establish a possible pathogenetic mechanism of preterm birth in women with threatened preterm birth on the basis of the revealed features of differentiation and functional activity of CD8⁺- lymphocytes at the systemic level

Materials and methods. The survey of women was carried out on the basis of the Federal State Budgetary Institution “V. Gorodkov Ivanovo Research Institute of Maternity and Childhood” of the Ministry of Health of the Russian Federation. A total of 126 women were examined, which were retrospectively divided into 2 main groups – women with threatened preterm birth(n = 68), which was divided into 2 subgroups – with the outcome of pregnancy preterm birth (n = 30) and timely delivery (n = 38). The control group included 58 women with uncomplicated pregnancy and who gave birth on time. In the CD8⁺-lymphocyte population, the content of central – Tcm (CD45RACD62L⁺), preterminally differentiated-Tem (CD45RACD62L^- ) and terminally differentiated-Temra (CD45RA⁺CD62L^- ) memory cells was determined. In all memory cell populations, the content of cells producing Granzyme B intracellularly was determined. The studies were performed using monoclonal antibodies (mAT) by flow cytometry on a FACSCanto II cytometer using the FACSDiva software (Becton Dickinson, USA).

The analysis of the features of the relative content of CD8⁺-lymphocytes in the main group of women, depending on the outcome of pregnancy, was carried out. When comparing patients with a clinic of threatened preterm birth, whose pregnancy ended prematurely, a higher content of CD8⁺-lymphocytes was revealed than in group c of women who gave birth in a timely manner, which indicates a high stimulation of cytotoxic T-lymphocytes in this group of women. With threatening preterm birth, there is an increase in the content of naive CD8+-lymphocytes in the peripheral blood. Data on the content of naive CD8⁺-lymphocytes in the peripheral blood of women with threatened preterm birth are practically absent. The increase in CD8⁺Tn levels is more pronounced in the subgroup of women with a favorable pregnancy outcome. Given this fact, it can be assumed that in women with preterm birth, a lower CD8⁺Tn is associated with their increased differentiation into effector T-lymphocytes with their subsequent migration to the placental zone. This process could determine the observed decrease in the level of terminally differentiated granzyme-producing CD8⁺-lymphocytes in a subgroup of women with a pregnancy outcome of preterm birth, which coincided with the literature data. 

1. Arenas-Hernandez M., Romero R., St. Louis D., Hassan S.S., Kaye E.B., Gomez-Lopez N. An imbalance between innate and adaptive immune cells at the maternal-fetal interface occurs prior to endotoxin-induced preterm birth. Cell. Mol. Immunol., 2016, Vol. 13, pp. 462-473.

2. Bhatti G., Romero R., Rice G.E., Fitzgerald W., Pacora P., Gomez-Lopez N., Kavdia M., Tarca A.L., Margolis L. Compartmentalized profiling of amniotic fluid cytokines in women with preterm labor. PLoS One, 2020, Vol. 15, no. 1, e0227881. doi:10.1371/journal.pone.0227881.

3. Brummelman J., Pilipow K., Lugli E. The Single-cell phenotypic identity of human CD8+ and CD4+ T Cells. Int. Rev.Cell Mol. Biol., 2018, Vol. 341, pp. 63-124.

4. Du M.R., Guo P.-F., Piao H.-L., Wang S.-C., Sun C., Jin L.-P., Tao Y., Li Y.-H., Zhang D., Zhu R., Fu Q., Li D.-J. Embryonic trophoblasts induce decidual regulatory T cell differentiation and maternal–fetal tolerance through thymic stromal lymphopoietin instructing dendritic cells. J. Immunol., 2014, Vol. 192, no. 4, pp. 1502-1511.

5. Frascoli M., Coniglio L., Witt R., Jeanty C., Fleck-Derderian S., Myers D.E., Lee T.H., Keating S., Busch M.P., Norris P.J., Tang Q., Cruz G., Barcellos L.F., Gomez-Lopez N., Romero R., MacKenzie T.C. Alloreactive fetal T cells promote uterine contractility in preterm labor via IFN-γ and TNF-α. Sci. Transl. Med., 2018, Vol. 10, no. 438, eaan2263. doi: 10.1126/scitranslmed.aan2263.

6. Gomez-Lopez N., Romero R., Arenas-Hernandez M., Schwenkel G., St. Louis D., Hassan S.S., Mial T.N. In vivo activation of invariant natural killer T cells induces systemic and local alterations in T-cell subsets prior to preterm birth. Clin. Exp. Immunol., 2017, Vol. 189, pp. 211-225.

7. Gomez-Lopez N., Romero R., Panaitescu B., Leng Y., Xu Y., Tarca A.L., Faro J., Pacora P., Hassan S.S, Hsu C.-D. Inéammasome activation during spontaneous preterm labor with intra-amniotic infection or sterile intra-amniotic inéammation. J. Perinat. Med., 2020, Vol. 48, no. 3, pp. 222-233.

8. Kim C.J., Romero R., Chaemsaithong P., Kim J.-S. Chronic inflammation of the placenta: definition, classification, pathogenesis, and clinical significance. Am. J. Obstet. Gynecol., 2015, Vol. 213, no. 4 Suppl., pp. S53-S69.

9. Maymon E., Romero R., Bhatti G., Chaemsaithong P., Gomez-Lopez N., Panaitescu B., Chaiyasit N., Pacora P., Dong Z., Hassan S.S., Erez O. Chronic inflammatory lesions of the placenta are associated with an upregulation of amniotic fluid CXCR3: A marker of allograft rejection. J. Perinat. Med., 2018, Vol. 46, no. 2, pp. 123-137.

10. Pique-Regi, R., Romero, R., Tarca, A. L., Sendler, E. D., Xu, Y., Garcia-Flores, V., Leng Y., Luca F., Hassan S.S., Gomez-Lopez N. Single cell transcriptional signatures of the human placenta in term and preterm parturition. Elife, 2019, Vol. 8, e52004. doi: 10.7554/eLife.52004.

11. Romero R., Chaemsaithong P., Chaiyasit N., Docheva N., Dong Z., Kim C.J., Kim Y.M., Kim J.-S., Qureshi F., Jacques S.M., Yoon B.H., Chaiworapongsa T., Yeo L., Hassan S.S., Erez O., Korzeniewski S.J. CXCL10 and IL-6: Markers of two different forms of intra-amniotic inflammation in preterm labor. Am. J. Reprod. Immunol., 2017, Vol. 78, no. 1, e12685. doi: 10.1111/aji.12685.

12. van Egmond A., van der Keur C., Swings G.M.J.S., Scherjon S.A., F.H. J. Claas 2. The possible role of virusspecific CD8+ memory T cells in decidual tissue. J. Reprod. Immunol., 2016, Vol. 113, pp. 1-8.

13. van der Zwan A., Bi K., Norwitz E.R., Crespo Â.C., Claas F.H., Strominger, J.L., Tilburgs, T. Mixed signature of activation and dysfunction allows human decidual CD8+ T cells to provide both tolerance and immunity. Proc. Natl Acad. Sci., 2018, Vol. 115, no. 2, pp. 385-390.

14. Voskoboinik I., Whisstock J.C., Trapani J.A. Perforin and granzymes: function, dysfunction and human pathology. Nat. Rev. Immunol., 2015, Vol. 15, no. 6, pp. 388-400.