Thymus Development and Function
The development of vaccines for the treatment of infectious diseases, cancer and autoimmunity depends on our knowledge of T-cell differentiation. Our group is focused on studying the development and role of the thymus, the organ responsible for the generation of T cells that are simultaneously responsive against pathogens and self-tolerant.
Thymic activity is not regular throughout life and deficits in T-cell production arise in several pathophysiological states, including with age, infection and chemotherapy. Besides, the failure in the deletion of autoreactive T cells in the thymus can lead to autoimmunity. Hence, the regular function of the thymus must be tightly controlled in vivo. Within the thymus, thymic epithelial cells (TECs) provide key inductive microenvironments for the development and selection of T cells that arise from hematopoietic progenitors. As a result, defects in TEC differentiation cause syndromes that range from immunodeficiency to autoimmunity, which makes the study of TECs of fundamental, and clinical, importance to understand immunity and tolerance induction. TECs are divided into two functionally distinct cortical (cTECs) and medullary (mTECs) subtypes, which derive from common bipotent TEC progenitors (TEPs).
We take a global approach to investigate TEC differentiation, which integrates the study of molecular processes taking place at the single-cell level to the analysis of in vivo mouse models. Using advanced research tools that include reporter, germ-line and cell-specific knock-out mice, organotypic cultures combined with thymic transplantations and transcriptomic, our major goals are to elucidate the molecular principles that control the lineage specification of TEPs into mature cTEC/mTEC Ultimately, understanding the development and function of TECs is crucial to comprehend how the immune system achieves the equilibrium between immunity and tolerance.
Thymic epithelial cells require p53 to support their long-term function in thymopoiesis in mice. Blood130(4):478-488, 2017. [Journal: Article] [CI: 9] [IF: 15,1]
DOI: 10.1182/blood-2016-12-758961 SCOPUS: 85026293874. .
Rodrigues P.M., Ribeiro A.R., Serafini N., Meireles C., Di Santo J.P., Alves N.L.,
Intrathymic deletion of IL-7 reveals a contribution of the bone marrow to thymic rebound induced by androgen blockade. Journal of Immunology200(4):1389-1398, 2018. [Journal: Article] [CI: 3] [IF: 4,7]
DOI: 10.4049/jimmunol.1701112 SCOPUS: 85044784393. .
Meireles C., Ribeiro A.R., Pinto R.D., Leitão C., Rodrigues P.M., Alves N.L.,
Thymic crosstalk restrains the pool of cortical thymic epithelial cells with progenitor properties. European Journal of Immunology47(6):958-969, 2017. [Journal: Article] [CI: 8] [IF: 4,2]
DOI: 10.1002/eji.201746922 SCOPUS: 85017500745. .
Ribeiro A.R., Rodrigues P.M., Meireles C., Di Santo J.P., Alves N.L.,
Thymocyte selection regulates the homeostasis of IL-7-expressing thymic cortical epithelial cells in vivo. Journal of Immunology191(3):1200-1209, 2013. [Journal: Article] [CI: 46] [IF: 5,4]
DOI: 10.4049/jimmunol.1203042 SCOPUS: 84880685834. .
Alves N.L., Huntington N.D., Mention J.J., Richard-Le Goff O., Di Santo J.P.,
Cutting edge: A thymocyte-thymic epithelial cell cross-talk dynamically regulates intrathymic IL-7 expression in vivo. Journal of Immunology184(11):5949-5953, 2010. [Journal: Article] [CI: 28] [IF: 5,7]
DOI: 10.4049/jimmunol.1000601 SCOPUS: 77953449167. .
Alves N.L., Huntington N.D., Rodewald H.R., Di Santo J.P.,
Thymic epithelial cells: the multi-tasking framework of the T cell "cradle". Trends in Immunology30(10):468-474, 2009. [Journal: Article] [CI: 39] [IF: 8,8]
DOI: 10.1016/j.it.2009.07.010 SCOPUS: 70349556314. .
Ribeiro A.R., Meireles C., Rodrigues P.M., Alves N.L.,
Intermediate expression of CCRL1 reveals novel subpopulations of medullary thymic epithelial cells that emerge in the postnatal thymus. European Journal of Immunology44(10):2918-2924, 2014. [Journal: Article] [CI: 20] [IF: 4]
DOI: 10.1002/eji.201444585 SCOPUS: 84925298291. .
Alves N.L., Ribeiro A.R.,
Thymus medulla under construction: Time and space oddities. European Journal of Immunology46(4):829-833, 2016. [Journal: Note] [CI: 8] [IF: 4,2]
DOI: 10.1002/eji.201646329 SCOPUS: 84962197424. .
Alves N.L., Takahama Y., Ohigashi I., Ribeiro A.R., Baik S., Anderson G., Jenkinson W.E.,
Serial progression of cortical and medullary thymic epithelial microenvironments. European Journal of Immunology44(1):16-22, 2014. [Journal: Review] [CI: 60] [IF: 4]
DOI: 10.1002/eji.201344110 SCOPUS: 84892472653. .
Alves N.L., Goff O.R.L., Huntington N.D., Sousa A.P., Ribeiro V.S.G., Bordack A., Vives F.L., Peduto L., Chidgey A., Cumano A., Boyd R., Eberl G., Di Santo J.P.,
Characterization of the thymic IL-7 niche in vivo. Proceedings of the National Academy of Sciences of the United States of America106(5):1512-1517, 2009. [Journal: Article] [CI: 93] [IF: 9,4]
DOI: 10.1073/pnas.0809559106 SCOPUS: 60849114415. .