Murine pregnancy leads to reduced proliferation of maternal thymocytes and decreased thymic emigration.

During mammalian pregnancy the maternal thymus undergoes significant involution, and then recovers in size after birth. The mechanism behind this involution is not known, but it has been suggested that elevated levels of hormones during pregnancy induce the involution. We have recently shown that injection of 17beta-oestradiol into mice causes loss of early thymocyte precursors and inhibits proliferation of developing thymocytes. This suggests that elevated oestrogen in pregnancy may contribute to thymic involution. We have investigated this idea by examining the fate of thymocytes during mouse pregnancy in much greater detail than has been previously reported. Looking over a broad time-course, we find that pregnancy does not affect thymocyte precursor populations in the bone marrow, but induces a profound loss of early thymic progenitors in the thymus as early as day 12 x 5 of pregnancy. This loss is accompanied by decreased thymocyte proliferation, which returns to normal 2-4 days postpartum. No enhancement of apoptosis is detectable at any stage of pregnancy. We also find that there is a reduction in recent thymic emigrants after oestrogen treatment and at day 17 x 5 of pregnancy, suggesting that thymic involution during pregnancy influences the peripheral T-cell repertoire. The similarities between oestrogen-mediated involution and pregnancy-mediated involution suggest that oestrogen is a significant contributor to loss of thymocyte cellularity during pregnancy, and probably functions primarily by reducing thymocyte proliferation.

Estrogen induces thymic atrophy by eliminating early thymic progenitors and inhibiting proliferation of beta-selected thymocytes.

Although it has been established that high levels of estrogen can induce thymic involution, the mechanism by which this happens is not known. We have found that daily i.p. injections of the synthetic estrogen 17-beta-estradiol reduce thymus cellularity by 80% over a period of 4-6 days. Although the atrophy is most strikingly observed in the CD4/CD8 double-positive (DP) thymic subset, the loss of thymocytes is not accompanied by a significant increase in thymocyte apoptosis, suggesting that direct killing of cells may not be the dominant means by which estrogens induce thymic atrophy. Instead, we find that estradiol drastically reduces the lineage-negative, Flt3(+)Sca-1(+)c-Kit(+) population in the bone marrow, a population that contains thymic homing progenitors. Within the thymus, we observe that estradiol treatment results in a preferential depletion of early thymic progenitors. In addition, we find that estradiol leads to a significant reduction in the proliferation of thymocytes responding to pre-TCR signals. Reduced proliferation of DN3 and DN4 cell subsets is likely the major contributor to the reduction in DP thymocytes that is observed. The reduction in early thymic progenitors is also likely to contribute to thymic atrophy, as we show that estradiol treatment can reduce the size of Rag1-deficient thymuses, which lack pre-TCR signals and DP thymocytes.

Early growth response gene 1 provides negative feedback to inhibit entry of progenitor cells into the thymus.

The size of the thymus can be greatly influenced by changes in the small number of early progenitors in the thymus. However, it is not known whether thymic cellularity feeds back to regulate the recruitment, survival, and expansion of progenitors. The transcription factor early growth response gene 1 (Egr1) has been implicated in controlling proliferation and survival in many cell types. We have previously shown that mice deficient in Egr1 have increased thymic cellularity. We now show that Egr1 regulates a negative feedback signal that controls the entry of cells into the thymus. Egr1-deficient mice have higher percentages of early T lineage progenitors in the thymus, yet Egr1-deficient mice have normal numbers of myelolymphoid progenitors in the bone marrow, and Egr1-deficient thymocytes show normal rates of apoptosis and proliferation at all stages of development. Evidence from mixed bone marrow chimeras shows that the ability of Egr1 to control progenitor recruitment is mediated by bone marrow-derived cells, but is not cell autonomous. Furthermore, Egr1-deficient thymuses have increased P-selectin expression. The data suggest that Egr1 mediates a feedback mechanism whereby the number of resident double negative thymocytes controls the entry of new progenitors into the thymus by regulating P-selectin expression on thymic endothelial cells.