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
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.