Sites of eTML
- Crossroads ofextrathymic lymphocytesmaturation pathways

Except the major sites of extrathymic T cells maturation like the intestine and liver, it is well known that pregnant uterus, decidua, microenvironments of malignant tissues, allogeneic transplants, autoimmune and infective focuses also can be real sites of eTLM. Because sites of eTLM in more cases are temporary and poorly anatomical defined, any similarity and/or differences between thymic and eTLM pathways are hardly for demonstrations. However, extrathymic pathway of lymphocyte maturation probably plays a pivotal role in immune mechanisms of autoimmune diseases, malignancies, pregnancy and response to microbes. At least, mechanism of eTLM can be one of the universal mechanisms of immune reactions control.

Liver and intestine contain large proportion of TCRγδ+cells as well as TCRαβ+cells, also contain DN cells and self-reactive oligoclones. These cells constitutively express the IL-2 receptor β-chain, and have a aa homodimer of CD8+, while intraepithelial lymphocytes TCRαβ+cells were mainly IL-2R β- and contained both DP cells and SG cells. CD4+ cells were more predominant than CD8+ cells in the liver, while CD8+ cells were persuasively predominant in the intestine (5,15). A specific cell population, the DP cells, normally present in liver and the thymus, but in liver the population shows significant increase in number during viral hepatitis. At the same time, no significant changes in T cell subpopulations were detected in the spleen. These observations suggest that viral infection could induce an early in situ stimulation of resident hepatic T cells, despite a peripheral immunodeficiency in the thymus and spleen (20). Pregnancy is the condition of Th2 cells domination and proliferative trophoblast toleration. Shift in domination of Th2 cells subpopulation happens in second phase of menstrual cycle and in early pregnancy. These events are results of immunosuppressive and immunomodulatory factors activity in pregnancy (21). However, some authors are of the opinion that shift in endometrial and decidual lymphocyte subpopulations are the result of eTLM (22).

In accordance with previous data, Lee et al. (23) have detected that population of tumor infiltrating lymphocytes contains about 15% of DP immature lymphocytes (23). These data maintained an opinion about tumor tissues like microenvironment of intensive eTLM. Although DP T cells are rarely present in human peripheral blood, the relative percentage of this lymphocyte population can increase spontaneously in healthy individuals and in persons suffering from certain disease conditions. These cells can also be found among those T cells infiltrating arthritic joints, rejected kidney grafts and certain tumors (24). Experiments with neonatally thymectomized showed that the mice fall victim to such autoimmune diseases as gastritis and pancreatitis with aging. Self-reactive T cell clones can be consistently generated in the absence of the thymus, and these clones via the extrathymic pathways and an alternative pathway probably are responsible for autoimmune disease induction (25).

After intraperitoneal inoculation with Listeria monocytogenes, TCRγδ+ cells appear in the peritoneal cavity preceding the appearance of TCRαβ+ cells. Such TCRγδ+ cells predominantly express T cell receptor TCRγ1/Vδ6, develop through an extrathymic pathway, and contribute to host defense against the bacteria (26). Results from other authors suggested that Th2-associated responses also can be induced by nematode infection in rats through the extrathymic recruitment and proliferation of CD4+CD8- SG TCRαβ+ T cells (27). Mouse hepatitis induced with virus type 3 is an excellent model for the study of thymic and extrathymic T cell subpopulation disorders induced during viral hepatitis. It was recently reported that, in addition to the intrathymic T-cell differentiation pathway, an extrathymic differentiation pathway of TCRαβ+ T lymphocytes exists in the liver, and becomes important under pathological situations such as autoimmune diseases, malignancies or hepatic bacterial infections (20).


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