Where Ideas Grow

Thymus Development and Function

ABOUT

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.

 

RESEARCH

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.

Cortical (green) and Medullary (red) microenvironments formed by Thymic Epithelial Cells in the Thymus.

Team

Selected Publications

Rodrigues P.M., Sousa L.G., Perrod C., Maceiras A.R., Ferreirinha P., Pombinho R., Romera-Cárdenas G., Gomez-Lazaro M., Senkara M., Pistolic J., Cabanes D., Klein L., Saftig P., Alves N.L.,
LAMP2 regulates autophagy in the thymic epithelium and thymic stroma-dependent CD4 T cell development. Autophagy19(2):426-439, 2023. [Journal: Article] [CI: 8] [IF: 13,3 (*)]
DOI: 10.1080/15548627.2022.2074105 SCOPUS: 85130879833

Rodrigues P.M., Ribeiro A.R., Perrod C., Landry J.J.M., Araújo L., Pereira-Castro I., Benes V., Moreira A., Xavier-Ferreira H., Meireles C., Alves N.L.,
Thymic epithelial cells require p53 to support their long-term function in thymopoiesis in mice. Blood130(4):478-488, 2017. [Journal: Article] [CI: 27] [IF: 15,1]
DOI: 10.1182/blood-2016-12-758961 SCOPUS: 85026293874

Ferreirinha P., Pinheiro R.G.R., Landry J.J.M., Alves N.L.,
Identification of fibroblast progenitors in the developing mouse thymus. Development149(10):, 2022. [Journal: Article] [CI: 3] [IF: 4,6]
DOI: 10.1242/dev.200513 SCOPUS: 85131106492

Rodrigues P.M., Peterson P., Alves N.L.,
Setting Up the Perimeter of Tolerance: Insights into mTEC Physiology. Trends in Immunology39(1):2-5, 2018. [Journal: Short Survey] [CI: 9] [IF: 13]
DOI: 10.1016/j.it.2017.11.001 SCOPUS: 85035084214

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: 8] [IF: 4,7]
DOI: 10.4049/jimmunol.1701112 SCOPUS: 85044784393

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: 72] [IF: 5,4]
DOI: 10.4049/jimmunol.1203042 SCOPUS: 84880685834

Ferreirinha P., Ribeiro C., Morimoto J., Landry J.J.M., Matsumoto M., Meireles C., White A.J., Ohigashi I., Araújo L., Benes V., Takahama Y., Anderson G., Matsumoto M., Alves N.L.,
A novel method to identify Post-Aire stages of medullary thymic epithelial cell differentiation. European Journal of Immunology51(2):311-318, 2021. [Journal: Article] [CI: 7] [IF: 6,7]
DOI: 10.1002/eji.202048764 SCOPUS: 85090990353

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: 23] [IF: 4,2]
DOI: 10.1002/eji.201746922 SCOPUS: 85017500745

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: 117] [IF: 9,4]
DOI: 10.1073/pnas.0809559106 SCOPUS: 60849114415

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: 78] [IF: 4]
DOI: 10.1002/eji.201344110 SCOPUS: 84892472653

Ongoing Projects

Princípios Moleculares envolvidos no desenvolvimento das células T e Indução de Tolerância no Timo: Definição do papel das proteínas de ligação ao RNA na especificação e função da linhagem das células epiteliais tímicas in vivo.
Reference: PTDC/MED-IMU/1416/2020
Proponent: Instituto de Investigação e Inovação em Saúde - Universidade do Porto
Sponsor: FCT - Fundação para a Ciência e a Tecnologia
From 29-MAR-21 to 31-DEC-24
Thymus regeneration: from thymic epithelial cell reprograming to development of T cells
Reference: EXPL/MED-IMU/1537/2021
Proponent: Instituto de Investigação e Inovação em Saúde - Universidade do Porto
Sponsor: FCT - Fundação para a Ciência e a Tecnologia
From 01-MAR-22 to 29-FEB-24
Molecular Control of Thymus Function via Foxn1: Implications for Immunomodulatory Therapies
Reference: PTDC/MED-IMU/0888/2021
Proponent: Instituto de Investigação e Inovação em Saúde - Universidade do Porto
Sponsor: FCT - Fundação para a Ciência e a Tecnologia
From 01-MAR-22 to 28-FEB-25
Controlo molecular da função do timo: Implicações para o desenvolvimento das células T e imunidade
Reference: Programa Pessoa - 2022.15027.CBM
Proponent: Instituto de Investigação e Inovação em Saúde - Universidade do Porto
Sponsor: FCT - Fundação para a Ciência e a Tecnologia
From 13-MAR-23 to 13-MAR-24
The molecular regulation of T cell development in the thymus: Implications for infectious diseases
Reference: la Caixa HR23-00380
Proponent: Instituto de Investigação e Inovação em Saúde - Universidade do Porto
Sponsor: "la Caixa" Foundation
From 31-DEC-23 to 31-DEC-26
Deciphering the impact of leukaemia on immunological fitness beyond disease
Reference: la Caixa HR23-00608
Proponent: Instituto de Investigação e Inovação em Saúde - Universidade do Porto
Sponsor: "la Caixa" Foundation
From 31-DEC-23 to 31-DEC-26