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Hypothesis that microbes, especially viruses, can be promoters of extrathymic (self)antigen-reactive …

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Crossroads of eTLM pathways
- Crossroads ofextrathymic lymphocytesmaturation pathways

Some authors propose the possibility that switching of the immune system from the thymus to the alternative eTLM sites might be regulated by the autonomic nervous system as well as by cytokines. Extrathymic T cells are very few in number at any extrathymic sites in adolescence, but they increase in number as a function of aging (5,15). This process probably is parallel with progression of thymic involution. Moreover, acute thymic atrophy always accompanies activation of eTLM. Therefore, reciprocal regulation between extrathymic T cells and thymus-derived T cells might be present.

Cytokines like IL-7 have very important role in extrathymic T cell development. Under influence of this cytokine, human hematopoietic stem cells can develop into mature TCRαβ+ lymphocytes and immature progenitors in the bone marrow of athymic mice (28). Extrathymic TCRαβ+ can be detected, but not TCRγδ+, in IL-7 gene-deleted animals, suggesting that alternative cytokines may be involved in eTLM (29,30). Porter and Malek (31) have discovered that eTLM is regulated by cytokines like IL-2, IL-7 and IL-15, but IL-2 is most important for thymic pathway according such as IL-15, most important for eTLM (31,32).

Extrathymic dendritic cells and APCs can be associated with eTLM and clonal selection as well as thymic dendritic cells and APCs. There is evidence about antigen- specific induction of apoptosis in CD4þ8þ thymocytes cultured in suspension, by thymic as well as splenic APCs. Thus, the recognition of antigen by CD4+8+ thymocytes may lead to deletion, suggesting that this is the central mechanism of tolerance induction, which is not limited by the antigen-presenting ability of the thymic stroma (33).

Steroid hormones probably can be activators of eTLM, at the same time; extrathymic matured lymphocytes are more resistant to steroids activity in relation to thymic lymphocytes (34).

Data about activation of eTLM by stress in adolescence indicate relationship between stress, steroids, thymic atrophy and eTLM. Most likely, majority of conditions with thymic atrophy like pregnancy and malignant tumors are accompanied with eTLM activation. Direction of eTLM probably depends upon many factors and microenvironmental status. To that effect, some of the factors that might be polarizing eTLM pathway probably are microbes, costimulatory molecules, Fas ligand, prostaglandine, sex hormones, heat shock proteins and expression of MHC molecules. After activation of eTLM center, microenvironmental conditions probably can determinate reactivity of extrathymic- derived lymphocytes, according to (self)antigen- reactive or antigen-protective way. For example, microbes and immunostimulatory factors like Th1 cytokines probably might be factors of eTLM polarization, according to (self)antigen-reactive manner of immune reaction. Allowing for this model, (self)antigen-reactive manner of eTLM possibly includes positive selection of (self)antigen-reactive thymus-independent lymphocytes, activation of thymus-dependent lymphocytes like CTL and Th1 cells, NK activity stimulation, suppression and/ or negative selection of Th2 and suppressor cells (Figs. 1 and 3).

In the events of microenvironmental domination of Th2 cytokines and other immunosuppressive/immunomodulatory factors, mechanism of eTLM probably includes negative selection of antigen-reactive thymusindependent lymphocytes, suppression of thymus-dependent lymphocytes like CTL and Th1 cells, NK activity suppression, activation and/or positive selection of Th2 antigen-reactive and suppressor cells (Figs. 2 and 3).

Hypothesis about eTLM as phenomenon of in situ lymphocytes maturation that includes mechanisms of clonal selection and changes in composition of lymphocyte subpopulations, may originate some models of immune reactivity in different conditions (Fig. 3).

Based on the described models of eTLM, participation of extrathymic-derived lymphocytes in autoimmunity or tumor, trophoblast and transplant rejections or escape probably is very considerable.

Autoimmunity may be the result of thymic involutive factors activity in coexist with activation of eTLM and microbes, especially viruses. Under these conditions, focuses of eTLM generate self-reactive thymus-independent lymphocytes, belike by positive selection mechanisms. At one time, activation of thymus-dependent CTL and Th1, and NK cells happens. Since pregnancy and malignancy are phenomena of thymus involution, similar processes may be included in mechanisms of miscarriages and tumor rejection.

As distinct from mechanisms of tumor escape or trophoblast escape in successful pregnancy probably are based upon thymic involution, activation of eTLM and interaction with many immunosuppressive/ immunomodulatory factors, but in the absence of microbes. Under these conditions, focuses of eTLM generate suppressor lymphocytes, during thymus-independent antigen- reactive clones die by apoptosis, belike by negative selection mechanisms. Inhibition of thymus-dependent CTL and Th1, and NK cells also happens. In addition, ability that eTLM participate in activation and/or positive selection of Th2 and Th3 cells in mechanisms of trophoblast and tumor escape as well existed.

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