CCL25 increases thymopoiesis after androgen withdrawal

Abstract

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. (Blood. 2008;112: 3255-3263) IntroductionImpaired thymopoiesis contributes to the immune deficiency after lymphopenia or allogeneic hematopoietic stem cell transplantation (HSCT). 1,2 The thymus is the primary site of new naive T-cell generation and the site of central tolerance induction where potentially autoreactive T cells are deleted. 3 Without thymic renewal during recovery from lymphopenia, an oligoclonal repertoire of T cells persists, leading to impaired clearance of infectious diseases and tumors, and increased rates of auto-or alloimmunity (graft-versus-host disease). [4][5][6][7][8] Thus, an understanding of the mechanisms underlying renewed thymopoiesis may be of critical importance to correcting thymic deficits after HSCT, AIDS therapies, and chemotherapeutic treatment for cancer.Androgen withdrawal presents a potential therapy to renew thymic function. Multiple studies have demonstrated that androgen withdrawal increases thymic size and thymocyte numbers in male mice. [9][10][11][12][13] These studies suggested that this enlargement represents enhanced thymic activity as evidenced by subsequent increases in naive T cells in peripheral organs. 12,14 Furthermore, transplant studies in mice and man have shown enhanced thymic recovery and increased peripheral recent thymic emigrants (RTE) after androgen withdrawal, consistent with overall augmented thymopoiesis. 12,15,16 However, the mechanism by which androgen withdrawal induces thymic recovery remains incompletely understood. Because thymic epithelial cells (TEC) and thymocytes possess functional androgen receptors, studies have focused on these cells as mediators of thymic enlargement associated with androgen withdrawal. 17,18 Initial studies into the thymic effects of androgen revealed rapid thymocyte apoptosis associated with thymic involution after androgen administration. 19,20 Conversely, androgen withdrawal has been shown to enhance proliferation of t...

Intrathymic progenitor cell transplantation across histocompatibility barriers results in the persistence of early thymic progenitors and T-cell differentiation

“…20,21,31,32 Conditions that increase expression of the CCR9 ligand, CCL25, on thymic epithelial cells will also enhance ETP immigration to the thymus. 33 In this context, it is interesting to note that the levels of CCL25 and P-selectin are decreased by 40% in ZAP-70-deficient vs WT thymi (as detected by quantitative reverse-transcription polymerase chain reaction; R.V. and V.Z., unpublished data), likely accounting for the decreased steady-state level of ETP in these mice.…”

Sex Steroid Ablation Enhances Hematopoietic Recovery following Cytotoxic Antineoplastic Therapy in Aged Mice

“…Furthermore, increased levels of the chemokine CCL25 can influence the uptake of progenitors from the circulation following SSA (79).…”

Feeding the fire: the role of defective bone marrow function in exacerbating thymic involution

“…Considering the role of S1P in HSC migration and homing [53,54], however, a greater role for S1P might be on the egress of these progenitors from the BM, limiting thymus function indirectly. Interestingly, following thymic regeneration mediated by sex steroid ablation there is both an increase in thymic export [40] and enhanced thymic CCL25 expression and receptivity [55].…”