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Thymic Involution Development in Two Different Models of Effects Of Effects of Castration on Thymocyte Development in Two Different Models of Thymic Involution This information is current as Tracy S. P. Heng, Gabrielle L. Goldberg, Daniel H. D. Gray, of October 3, 2021. Jayne S. Sutherland, Ann P. Chidgey and Richard L. Boyd J Immunol 2005; 175:2982-2993; ; doi: 10.4049/jimmunol.175.5.2982 http://www.jimmunol.org/content/175/5/2982 Downloaded from References This article cites 64 articles, 27 of which you can access for free at: http://www.jimmunol.org/content/175/5/2982.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 3, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Effects of Castration on Thymocyte Development in Two Different Models of Thymic Involution1 Tracy S. P. Heng,2 Gabrielle L. Goldberg,2 Daniel H. D. Gray,2 Jayne S. Sutherland, Ann P. Chidgey,2 and Richard L. Boyd2,3 Age-associated thymic involution is accompanied by decreased thymic output. This adversely affects general immune competence and T cell recovery following cytoreductive treatments such as chemotherapy. A causal link between increasing sex steroids and age-related thymic atrophy is well established. Although castration has been demonstrated to regenerate the atrophied thymus, little is known about how this is initiated or the kinetics of thymocyte regeneration. The present study shows that although castration impacts globally across thymocyte development in middle-aged mice, the regenerative effects are initiated in the im- mature triple-negative compartment and early T lineage progenitors (ETP). Specifically, there was a reduction in number of ETP with age, which was restored following castration. There was, however, no change in ETP reconstitution potential in ETP at this Downloaded from age or following castration. Furthermore, in a chemotherapy-induced model of thymic involution, we demonstrate castration enhances intrathymic proliferation and promotes differentiation through the triple-negative program. Clinically, reversible sex steroid ablation is achieved hormonally, and thus presents a means of ameliorating immune inadequacies, for example, following chemotherapy for bone marrow transplantation. By improving our understanding of the kinetics of thymic recovery, this study will allow more appropriate timing of therapy to achieve maximal reconstitution, especially in the elderly. The Journal of Immunology, 2005, 175: 2982–2993. http://www.jimmunol.org/ t is well documented that the adaptive immune system dete- ation of these cells. However, transfer of young BM into irradiated riorates with age (1, 2). Much of the decline is associated aged mice did not restore thymic architecture (13) and produced a I with changes in T cell populations and function, which, in smaller thymus than when young thymus was reconstituted with turn, can be attributed to degeneration of the thymus. Thymic at- old BM (12). This indicates the involuted thymic microenviron- rophy is characterized by a decrease in size, weight, and cellularity ment also has a profound impact on thymocyte development. with disruption of structure and function of the organ, culminating BM-derived precursors periodically seed the thymus, maintain- in a decrease of emigrants entering the peripheral T cell pool (3). ing thymic lymphopoiesis throughout adult life (14, 15). The ear- by guest on October 3, 2021 The reduction in naive T cell output from the thymus initiates the liest intrathymic precursors are contained in the CD3Ϫ homeostatic expansion of pre-existing memory cells (4–6), nar- CD4ϪCD8Ϫ triple-negative (TN) compartment, which can be rowing the TCR repertoire (7, 8) and decreased responses to new subdivided into four populations on the basis of CD44 and CD25 or previously encountered Ags (9). ϩ expression (16). The most immature thymocytes are CD44 It has been proposed that the decline of thymic function with age Ϫ ϩ ϩ CD25 (TN1), which up-regulate CD25 to become CD44 CD25 results from either alterations in precursors migrating from the (TN2). The transition from TN2 to CD44ϪCD25ϩ (TN3) is ac- bone marrow (BM)4 to the thymus or changes in thymocyte de- companied by TCR␤-chain gene rearrangement (16). Cells that velopment. BM-derived precursors have been shown to be quan- have productively rearranged their ␤-chain commence TCR␣-chain titatively and qualitatively compromised with age, with old BM Ϫ Ϫ having diminished reconstitution capacity in fetal thymic organ gene rearrangement and differentiate into CD44 CD25 (TN4) (17). This last TN stage is relatively transient with cells differentiating into cultures (FTOC) (10, 11) and in BM transplantation (BMT) (12) ϩ ϩ ϩ compared with young BM. This suggests an age-associated defect CD4 CD8 double-positive (DP) cells, and, in turn, mature CD4 or ϩ in either the entry of progenitor cells or the intrathymic prolifer- CD8 single-positive (SP) thymocytes ready for export. In aged mice, evidence for a lesion at an early step in thymocyte development stemmed from the finding of a decrease in the num- Department of Immunology, Monash University, Central and Eastern Clinical School, Alfred Hospital, Prahran, Australia ber of TN2 and downstream TN cells (18). Because there was no Received for publication January 20, 2005. Accepted for publication June 13, 2005. change in number of TN1 cells with age, it suggested a block The costs of publication of this article were defrayed in part by the payment of page specifically at the TN1 to TN2 transition rather than a defect in charges. This article must therefore be hereby marked advertisement in accordance precursor recruitment. However, the TN1 subset is heterogenous with 18 U.S.C. Section 1734 solely to indicate this fact. and includes cells that do not have T potential (19). Further dis- 1 This work was supported by a grant from Norwood Immunology. section of TN1 has identified a minute fraction with highly en- 2 Current address: Monash Immunology and Stem Cell Laboratories, Monash Uni- riched T precursor potential called early T lineage progenitors versity, Wellington Road, Clayton, Victoria 3800, Australia. (ETP) (20). More recently, Min et al. (21) demonstrated age-re- 3 Address correspondence and reprint requests to Dr. Richard L. Boyd, Monash Im- munology and Stem Cell Laboratories, Monash University, Wellington Road, Clayton lated developmental defects in ETP, indicating thymic involution VIC 3800, Australia. E-mail address: [email protected] initiates at an earlier stage than previously appreciated. 4 Abbreviations used in this paper: BM, bone marrow; BMT, BM transplantation; Cx, Thymic atrophy becomes most evident from the onset of pu- castrated; Cy, cyclophosphamide; DP, double positive; ETP, early T lineage progen- itor; FTOC, fetal thymic organ culture; KGF, keratinocyte growth factor; SP, single berty, predominantly due to elevated sex steroid levels (22, 23). positive; TEC, thymic epithelial cell; TN, triple negative. Accordingly, surgical or chemical castration of aged animals Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 The Journal of Immunology 2983 caused regeneration of the thymus, which was reversed by admin- lyzed on a multiparameter FACSCalibur (BD Biosciences) using CellQuest istration of synthetic sex steroids (24–28). Castrated (Cx) male software (BD Biosciences). Ϫ mice showed enhanced proliferation of CD3 thymocytes (29). ETP purification Conversely, androgen administration to intact female and Cx male mice led to increased thymocyte apoptosis (30). Receptors for es- Collagenase digestion of freshly dissected thymi (10 pooled for each group) was performed, as described previously (36). Thymocytes were trogen, androgen, and progesterone are found on both thymocytes incubated with saturating concentrations of anti-CD3 (KT3) and anti-CD8 and thymic stromal cells (31–35). However, a recent study dem- (53-6.7). Ab-bound cells were removed with magnetic beads conjugated to onstrated chimeric mice with androgen receptor-defective stroma sheep anti-rat IgG (Dynal Biotech). The negative fractions were then la- and wild-type thymocytes did not undergo thymic atrophy (31). It beled for ETP, as described above, with anti-CD44 CyChrome substituted therefore appears that the thymic stroma is the main cellular target by anti-CD44 FITC. Cells were sorted on a multiparameter FACStar (BD Biosciences), counted, and analyzed to determine cell recovery and purity. for sex steroid-, or, at least, androgen-induced thymic atrophy. The well-documented cellular regeneration that occurs in the FTOC aged thymus following sex steroid ablation sets a foundation for FTOC were established, as previously described (37). Briefly, E15 thymic rejuvenating thymic function in immunocompromised
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