Thymic-dependent differentiation of bone marrow (BM)-derived progenitors and thymic-independent antigen-driven peripheral expansion of mature T cells represent the 2 primary pathways for T-cell regeneration. These pathways are interregulated such that peripheral T-cell expansion is increased in thymectomized versus thymus-bearing hosts after bone marrow transplantation (BMT). This study shows that this interregulation is due to competition between progeny of these 2 pathways because depletion of thymic progeny leads to increased peripheral expansion in thymus-bearing hosts. To test the hypothesis that competition for growth factors modulates the magnitude of antigen-driven peripheral expansion during immune reconstitution in vivo, a variety of T-cell active cytokines were administered after BMT. Of the cytokines (interleukins) tested (IL-3, IL-12, IL-6, IL-2, and IL-7), IL-2 modestly increased peripheral expansion in the face of increasing numbers of thymic emigrants, whereas IL-7 potently accomplished this. This report also demonstrates that the beneficial effect of IL-7 on immune reconstitution is related to both increases in thymopoiesis as well as a direct increase in the magnitude of antigen-driven peripheral expansion. Therefore, the administration of exogenous IL-7, and to a lesser extent IL-2, abrogates the down-regulation in antigendriven peripheral expansion that occurs in thymus-bearing hosts after BMT. These results suggest that one mechanism by which T-cell-depleted hosts may support antigen-driven T-cell expansion in vivo is via an increased availability of T-cellactive cytokines to support clonal expansion. (Blood. 2001;97:1491-1497)

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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...

To study interleukin-7 (IL-7) in early thymocyte development, we generated mice transgenic (Tg) for the IL-7 gene under control of the lck proximal promoter. Founder line TgA, with the lowest level of IL-7 overexpression, showed enhanced ␣␤ T-cell development. In contrast, in the highest overexpressing founder line, TgB, ␣␤ T-cell development was disturbed with a block at the earliest intrathymic precursor stage. This was due to decreased progenitor proliferation as assessed by Ki-67 staining and in vivo bromodeoxyuridine (BrdU) incorporation. Bcl-2 was upregulated in T-cell-committed progenitors in all Tg lines, and accounted for greater numbers of double positive (DP), CD4 single positive (SP), and CD8SP thymocytes in TgA mice where, in contrast to TgB mice, thymocyte progenitor proliferation was normal. Mixed marrow chimeras using TgB ؉ and congenic mice as donors, and experiments using anti-IL-7 monoclonal antibody (MAb) in vivo, confirmed the role of IL-7 protein in the observed TgB phenotype. In conclusion, at low Tg overexpression, IL-7 enhanced ␣␤ T-cell development by increasing thymocyte progenitor survival, while at high overexpression IL-7 reduces their proliferation, inducing a dramatic block in DP production. These results show for the first time in vivo a dose effect of IL-7 on ␣␤ T-cell development and have implications for IL-7 in the clinical setting. IntroductionInterleukin-7 (IL-7) is a nonredundant cytokine in thymic development. It has been implicated in both proliferation and survival of early T cells. [1][2][3] After the transition from the multipotent to the T-cell-committed stage, thymocyte progenitors become dependent on IL-7 for normal cell cycle progression and cell survival through inhibition of apoptosis via up-regulation of the Bcl-2 expression. 1 Consequently, in several mouse models of IL-7 signal disruption such as IL-7 Ϫ/Ϫ , 2 IL-7 receptor ␣ Ϫ/Ϫ (IL-7R␣ Ϫ/Ϫ ), 3,4 ␥c Ϫ/Ϫ , 5-7 Jak3 Ϫ/Ϫ , [8][9][10] and Jak1 Ϫ/Ϫ , 11 progression beyond double negative-2 (DN2) stage is severely diminished. However, despite its role on proliferation, studies evaluating the need for IL-7 during lymphocyte development led to the conclusion that the primary role of this cytokine was rather in maintaining cell survival. 12 Additionally, IL-7 controls T-cell receptor ␥ (TCR␥) rearrangement by regulating locus accessibility, 13 such that ␥␦ T-cell production is abrogated in the absence of IL-7 signaling, 4,5,9,13-15 demonstrating a complete reliance on IL-7 by this lineage.Many in vitro studies have shown an effect of IL-7 on thymocyte progenitors. [16][17][18][19] However, the effect of IL-7 on ␣␤ T-cell development yielded somewhat conflicting results. Varas et al observed, with rat fetal thymic organ culture (FTOC) grown in the presence of 2000 U/mL IL-7, an enhancement of ␣␤ thymocyte maturation. 19 In contrast, Plum et al's study, which used mouse FTOC treated with different doses of human recombinant IL-7 (rIL-7, 100-5000 U/mL), showed significantly lower numbers of ␣␤ T cells with increasing I...