Extrathymic pathways of T-cell differentiation and immunomodulation

It is well established that the thymus is an essential organ for the suppor t of T-cell differentiation. However, some T cells, termed extrathymic T ce lls, have been found to differentiate without such support by the thymus. T he major sites of these T cells are the intestine and liver. Subsequent stu dies have revealed that extrathymic T cells are also present in the uterus and exocrine glands (e.g., the salivary gland). Depending on the sites, ext rathymic T cells have some distinct properties as well as some common prope rties. For example, all extrathymic T cells have a TCR-CD3 complex similar to thymus-derived T cells. Extrathymic T cells comprise both alpha betaT ce lls and gamma deltaT cells. Although extrathymic T cells are very few in nu mber at any extrathymic sites in youth, they increase in number as a functi on of age. This phenomenon seems to occur in parallel with thymic involutio n. Even in youth, extrathymic T cells are activated in number and function by stress, in autoimmune diseases, and during pregnancy. Acute thymic atrop hy always accompanies this activation. Therefore, reciprocal regulation bet ween extrathymic T cells and thymus-derived T cells might be present. We hy pothesize that extrathymic T cells are intimately associated with innate im munity and that the mechanisms underlying autoimmune diseases and intracell ular infection (e.g., malaria) cannot be properly understood without introd ucing the concept of extrathymic T cells. (C) 2001 Elsevier Science B.V. Al l rights reserved.