Extrathymic pathways of T-cell differentiation and immunomodulation

It is well established that the thymus is an essential organ for the support of T-cell differentiation. However, some T cells, termed extrathymic T cells, have been found to differentiate without such support by the thymus. The major sites of these T cells are the intestine and liver. Subsequent studies have revealed that extrathymic T cells are also present in the uterus and exocrine glands (e.g., the salivary gland). Depending on the sites, extrathymic T cells have some distinct properties as well as some common properties. For example, all extrathymic T cells have a TCR-CD3 complex similar to thymus-derived T cells. Extrathymic T cells comprise both alpha beta T cells and gamma delta T cells. Although extrathymic T cells are very few in number at any extrathymic sites in youth, they increase in number as a function of age. This phenomenon seems to occur in parallel with thymic involution. Even in youth, extrathymic T cells are activated in number and function by stress, in autoimmune diseases, and during pregnancy. Acute thymic atrophy always accompanies this activation. Therefore, reciprocal regulation between extrathymic T cells and thymus-derived T cells might be present. We hypothesize that extrathymic T cells are intimately associated with innate immunity and that the mechanisms underlying autoimmune diseases and intracellular infection (e.g., malaria) cannot be properly understood without introducing the concept of extrathymic T cells.