Although many self-reactive clones are deleted in the thymus, not all self-antigens will be found there. Antigen-presenting cells can exert a second level of tolerance induction. In order for a T cell to become activated, it requires two fundamentally different types of stimuli: one is antigen specific and is given by interaction of the T-cell receptor with antigen-MHC complex, and the other is antigen non-specific and depends on the engagement of secondary activation/adhesion molecules on the T-cell surface by appropriate counter-receptors on the stimulating antigen-presenting cell. Without correct co-stimulation T cells can become unreactive (anergic). The full extent of the molecular signals transmitting these 'co-stimulation' signals remains unknown, although interaction between the CD80(B7)-CD28 family of molecules is very important. The conditions regulating the expression of co-stimulatory molecules is also unknown, but it is clear that their expression is limited to a very few cell types and is regulated by the microenvironment surrounding the antigen-presenting cell, particularly by the extent of an inflammatory response. Thus responsiveness can be limited to appropriate sites of the body (e.g. lymphoid tissue) and to situations where antigen is found in the context of tissue damage.
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