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Thymus Growth an Epithelial Progenitor Pool Regulates An Epithelial Progenitor Pool Regulates Thymus Growth William E. Jenkinson, Andrea Bacon, Andrea J. White, Graham Anderson and Eric J. Jenkinson This information is current as of October 1, 2021. J Immunol 2008; 181:6101-6108; ; doi: 10.4049/jimmunol.181.9.6101 http://www.jimmunol.org/content/181/9/6101 Downloaded from References This article cites 35 articles, 16 of which you can access for free at: http://www.jimmunol.org/content/181/9/6101.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • 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 1, 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 © 2008 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology An Epithelial Progenitor Pool Regulates Thymus Growth1 William E. Jenkinson, Andrea Bacon, Andrea J. White, Graham Anderson, and Eric J. Jenkinson2 Thymic epithelium provides an essential cellular substrate for T cell development and selection. Gradual age-associated thymic atrophy leads to a reduction in functional thymic tissue and a decline in de novo T cell generation. Development of strategies tailored toward regeneration of thymic tissue provides an important possibility to improve immune function in elderly individuals and increase the capacity for immune recovery in patients having undergone bone marrow transfer following immunoablative therapies. In this study we show that restriction of the size of the functional thymic epithelial progenitor pool affects the number of mature thymic epithelial cells. Using an embryo fusion chimera-based approach, we demonstrate a reduction in the total number of both embryonic and adult thymic epithelium, which relates to the initial size of the progenitor cell pool. The inability of thymic epithelial progenitor cells to undergo sufficient compensatory proliferation to rescue the deficit in progenitor numbers suggests that in addition to extrinsic regulation of thymus growth by provision of growth factors, intrinsic factors such as a Downloaded from proliferative restriction of thymic epithelial progenitors and availability of progenitor cell niches may limit thymic epithelial recovery. Collectively, our data demonstrate an important level of regulation of thymic growth and recovery at the thymic epithelial progenitor level, providing an important consideration for developing methods targeted toward inducing thymic regeneration. The Journal of Immunology, 2008, 181: 6101–6108. ge-related changes in the immune system contribute to damage. A key factor in this is defining the nature and persistence http://www.jimmunol.org/ an overall reduction in immune responsiveness, leading of epithelial stem or progenitor cell activity throughout the life of A to increased susceptibility to infectious disease (1). Of the thymus. During initial thymus organogenesis in the murine these changes, age-related thymus atrophy has a profound effect embryo, both cortical and medullary epithelial lineages are known on the continued generation of naive T cells and results in a pe- to arise from a common progenitor population exclusively derived ripheral T cell pool containing dominant memory T cell clones, a from the endodermal germ layer (11–13). Within the thymic pri- process that limits diversity and ultimately reduces the capacity for mordium, initial differentiation of thymic epithelium from a bipo- vaccination-based strategies (2–5). Additionally, the capacity for T tent progenitor to cortical and medullary lineages is dependent on cell-mediated immune recovery following ablative therapies and the action of the transcription factor FoxN1, and this can occur bone marrow transfer declines with age in humans (6), most likely independently of thymocyte interactions within the embryo (14, by guest on October 1, 2021 occurring as a result of a reduced capacity of the aged thymus to 15). Additionally, mice bearing a hypomorphic allele of FoxN1 process T cell progenitors. Several lines of evidence indicate that have demonstrated an ongoing role for this transcription factor in a reduction in the epithelial compartment of the aged thymus is a controlling thymocyte-dependent stages of thymic epithelial mat- major factor in its ability to efficiently process and select mature T uration and maintenance (16, 17). However, the ongoing persis- cells. For example, a reduction in the proportion of medullary thy- tence and identity of progenitor activity at later developmental mic epithelium essential for negative selection of autoreactive T stages into the adult remain unclear (18). Recently, two different cell clones occurs with increasing age (7), while limiting the avail- mechanisms regulating organ size and regenerative capacity have ability of thymic epithelial cell niches directly affects thymic T cell been defined and shown to apply to different organs, even when production (8). Importantly, while the regenerative capacity of the such organs are of the same embryonic germ layer origin (19). aged thymus can be revealed in a variety of models (9, 10), neither Thus, in liver, reducing the epithelial progenitor pool during or- the mechanisms regulating this process nor the cell types being ganogenesis is rapidly compensated by increased expansion of the targeted are fully understood. remaining progenitors so that the organ still achieves normal size, Against this background, it is important to understand the mech- consistent with its known regenerative capacity. In contrast, re- anisms regulating the growth and size of the thymic epithelial ducing the functional progenitor pool allocated to the pancreas- compartment and its potential for regeneration following aging or forming domain of embryonic endoderm is not rescued by com- pensatory proliferation, resulting in a smaller organ, suggesting that the proliferative capacity of pancreatic epithelial progenitors is Medical Research Council Centre for Immune Regulation, Institute for Biomedical restricted and finite. Research, Medical School, University of Birmingham, Birmingham, United Kingdom In this study we have investigated whether the thymus, where Received for publication April 28, 2008. Accepted for publication August 20, 2008. the epithelium is also of an endodermal origin, conforms to either The costs of publication of this article were defrayed in part by the payment of page of these models of organ size determination. To do this, we have charges. This article must therefore be hereby marked advertisement in accordance utilized embryo fusion chimeras formed between wild-type (WT)3 with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported by a Leverhulme Early Career Fellowship (to W.E.J.) and an Medical Research Council Programme Grant (to E.J.J. and G.A.). 3 Abbreviations used in this paper: WT, wild type; E, embryonic day; EpCAM, ep- 2 Address correspondence and reprint requests to Dr. William Jenkinson, Medical ithelial cell adhesion molecule; eYFP, enhanced yellow fluorescent protein, TEC, Research Council Centre for Immune Regulation, Institute for Biomedical Research, thymic epithelial cell. Medical School, University of Birmingham, Birmingham B15 2TT, United Kingdom. E-mail address: [email protected] Copyright © 2008 by The American Association of Immunologists, Inc. 0022-1767/08/$2.00 www.jimmunol.org 6102 AN EPITHELIAL PROGENITOR POOL REGULATES THYMUS GROWTH Downloaded from http://www.jimmunol.org/ by guest on October 1, 2021 FIGURE 1. Generation of embryo fusion chimeric mice. A, Fusion chimeras were generated by aggregation of one 8-cell stage embryo from either donor in microwells (left panel), allowing rapid formation of a fused embryo (middle panel). Further in vitro culture resulted in formation of blastocysts of normal appearance (right panel) (magnification ϫ25). Fused blastocysts were subsequently transferred to pseudopregnant female hosts. B, Confirmation of chimera generation was performed through assessment of eYFP mosaicism in embryos of WT/FoxN1Ϫ/Ϫ mice. Additionally, chimerism was readily apparent in adult mice as indicated by overt coat chimerism in eYFPϩ(WT):eYFPϪ(WT) mice. C, Assessment of chimerism in thymic epithelium was performed through analysis of thymi from eYFPϩ(WT):eYFPϪ(WT) chimeras shown by FACS analysis. FACS plots gated on CD45Ϫ thymic stromal cells. Levels of chimerism within a single WT/FoxN1Ϫ/Ϫ adult chimera were determined within EpCAMϩ submandibular salivary gland (D) and within gated thymic cellular compartments of CD45ϩ thymocytes (i), CD45ϪEpCAMϩ thymic epithelium (ii), and CD45ϪEpCAMϪ thymic mesenchyme (iii)(E). mice expressing enhanced yellow fluorescent protein (eYFP) in all genitors can compete with WT progenitors for allocation into the tissues under the control of the Rosa26 promoter and FoxN1-de- thymic-forming domain of endoderm in chimeric individuals. Due ficient nude mice (non-eYFP), allowing the contribution
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