In addition to T cell differentiation in the thymus, we have recently reported that extrathymic T cell differentiation occurs preferentially in the sinusoids of the liver. Although this extrathymic pathway is relatively minor in normal mice, it becomes predominant in mice with autoimmune diseases, athymic mice, and aged mice. In the present study, injection of normal male C3H/He mice, 6-8 wk of age, with 1 mg of estrogen resulted in an increase in mononuclear cells (MNC) yielded from the liver and a drastic decrease in thymocytes approximately 10 d after such injection. This unique modulation was not observed with hydrocortisone injection (5 mg/mouse, i.p.) nor with irradiation (5 Gy/mouse). Rather, these immunosuppressive treatments induced a simultaneous decrease in cell number in both the liver and thymus. A time-kinetics study on the cell number and spontaneous cell proliferation revealed that an increase in spontaneous cell proliferation in the liver preceded the increase in the number of liver MNC, and a decrease in spontaneous cell proliferation in the thymus preceded the decrease in the number of thymocytes. At this time, an enrichment of alpha/beta T cells with intermediate T cell receptors (TCRs), including forbidden T cell oligoclones and V beta 8+ cells, which are characterized as extrathymic alpha/beta T cells with unique properties, took place in the liver. On the other hand, the thymic atrophy induced by estrogen resulted in a prominent decrease in immature double-positive (CD(4+)8+) alpha/beta T cells with dull TCRs. These results indicate that estrogen administration activates an extrathymic pathway of T cell differentiation in the liver and reciprocally inactivates the intrathymic pathway. As extrathymic T cells have unique characteristics such as autoreactivity, the present findings might be intimately related to a female predominance of autoimmune diseases and suggest a possible role of estrogen in this phenomenon.

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