Sir Henry Dale Fellow
T-cells play essential roles in immune responses. Antigen recognition by naive T-cells enables efficient responses against new immune challenges, and differentiation into long- term memory T-cells is the basis of vaccination. Dysregulated T-cell development results in diverse immunologically mediated diseases ranging from immunodeficiency to autoimmunity. Generation of T-cells occurs exclusively in the thymus, thus, this organ dictates the immunological competence of the host. However, T-cell development is not constant throughout life, and the thymus undergoes age-related involution that results in progressive deterioration of T-cell output, in addition to acute atrophy under multiple stressors such as infection, pregnancy, chemotherapy and malnutrition.
Age-associated loss of thymic function corresponds with alterations in T-cells observed with aging. These changes may underlie the loss of immunocompetence with age, however, this remains unknown because of limited models allowing efficient prevention or reversal of involution. Changes in thymic size throughout life are controlled by thymic epithelial cells (TECs), including the decline in thymic tissue with age. The transcriptional assessment of TECs through development facilitated the generation of genetically altered mouse models in which thymic involution can be prevented or reversed.
The Cowan lab will use these newly generated models to establish the contribution thymic atrophy has on underlying age-related immune defects. We will explore if restoring thymic function alters peripheral T-cell populations and consequently T-cell responses of aging hosts when immune challenged. Moreover, the Cowan lab is interested in exploring the role of TECs in orchestrating this involution process. Our work aims to better understand the mechanisms underlying immune aging, so as to improve immune protection in aged individuals.
- Selected publications
- Cowan JE, Takahama Y, Bhandoola A, and Ohigashi, I. Postnatal Involution and Counter-Involution of the Thymus. Frontiers in Immunology. 2020 May 12. PMID: 32477366
- Cowan JE, Malin J, Zhao Y, O. Seedhom M, Harly C, Ohigashi I, Kelly M, Takahama Y, Yewdell J, Cam M, and Bhandoola A. Myc Controls A Distinct Transcriptional Program in Fetal Thymic Epithelial Cells That Determines Thymus Growth. Nature Communications. 2019 Dec 02. PMID: 31792212
- Larsen BM, Cowan JE, Wang Y, Tanaka Y, Zhao Y, Voisin B, Constantinides MG, Nagao K, Belkaid Y, Awasthi P, Takahama Y and Bhandoola A. Identification of an Intronic Regulatory Element Necessary for Tissue-Specific Expression of Foxn1 in Thymic Epithelial Cells. J Immunol. 2019 June 26. PMID: 31243087
- Cowan JE, Baik S, McCarthy NI, Parnell SM, White AJ, Jenkinson WE, Anderson G. Aire controls the recirculation of murine Foxp3+ regulatory T-cells back to the thymus. Eur J Immunol. 2017 Dec 29. PMID: 29285761
- Cowan JE, McCarthy N.I, Anderson G. CCR7 Controls Thymus Recirculation, but Not Production and Emigration, of Foxp3+ T Cells. Cell Reports. 2016 Feb14. PMID: 26832402
- McCarthy N.I, Cowan JE, Nakamura K, Bacon A, Baik S, White AJ, Parnell SM, Jenkinson EJ, Jenkinson WE, Anderson G. Osteoprotegerin-Mediated Homeostasis of Rank+ Thymic Epithelial Cells Does Not Limit Foxp3+ Regulatory T Cell Development. J Immunol. 2015 Sep 7. PMID: 26254339
- Cowan JE, Jenkinson WE, Anderson G. Thymus medulla fosters generation of natural Treg cells, invariant γδ T cells, and invariant NKT cells: What we learn from intrathymic migration. Eur J Immunol. 2015 Feb 13. PMID: 25615828
- Cowan JE, McCarthy N.I, Parnell SM, White AJ, Bacon A, Serge A, Irla M, Lane PJ, Jenkinson EJ, Jenkinson WE, Anderson G. Differential Requirement for CCR4 and CCR7 During the Intrathymic Development of Innate and Adaptive abT-cells. J Immunol. 2014 Aug 1. PMID: 24990081
- Cowan JE, Parnell SM, Nakamura K, Caamano JH, Lane PJL, Jenkinson EJ, Jenkinson WE, Anderson G. The thymic medulla is required for Foxp3+ regulatory but not conventional CD4+ thymocyte development. J Exp Med. 2013 April 8. PMID: 23530124
- Desanti GE, Cowan JE, Baik S, Parnell SM, White AJ, Penninger JM, Lane PJ, Jenkinson EJ, Jenkinson WE, Anderson G. Developmentally regulated availability of RANKL and CD40 ligand reveals distinct mechanisms of fetal and adult cross-talk in the thymus medulla. J Immunol. (2012) Dec 15. PMID: 23152561
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