CCL25 increases thymopoiesis after androgen withdrawal.
Although studies have demonstrated that androgen withdrawal increases thymic size, molecular mechanisms underlying this expansion remain largely unknown. We show that decreased androgen signaling leads to enhanced immigration of bone marrow T-cell precursors, as manifested by both an early increase of early thymic progenitors (ETP) and improved uptake of adoptively transferred quantified precursors into congenic castrated hosts. We provide evidence that the ETP niche is enhanced after androgen withdrawal by proliferation of UEA(+) thymic epithelial cells (TEC) and increased TEC production of CCL25, a ligand critical for ETP entry. Moreover, the greatest increase in CCL25 production is by UEA(+) TEC, linking function of this subset with the increase in ETP immigration. Furthermore, blockade of CCL25 abrogated the effects of castration by impairing ETP entry, retarding immature thymocyte development, limiting increase of thymic size, and impairing increase of thymopoiesis. Taken together, these findings describe a cohesive mechanism underlying increased thymic productivity after androgen withdrawal.
Williams
Kirsten M
KM
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. williaki@mail.nih.gov
Lucas
Philip J
PJ
Bare
Catherine V
CV
Wang
Jiun
J
Chu
Yu-Waye
YW
Tayler
Ezekiel
E
Kapoor
Veena
V
Gress
Ronald E
RE
D000728:Androgens / Q000378:metabolism*; D000818:Animals; D002465:Cell Movement; D049109:Cell Proliferation; D002469:Cell Separation; D019742:Chemokines, CC / Q000378:metabolism*; D015331:Cohort Studies; D004847:Epithelial Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D011485:Protein Binding; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism*
D000728:Androgens; C108074:CCL25 protein, human; D019742:Chemokines, CC