Our laboratory 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 of T cells that arise from hematopoietic precursors. As a result, genetic defects that impair normal TEC differentiation are linked to immunodeficiency and autoimmunity, which makes the study of TECs of fundamental, and clinical, importance to understand the normal development and response of the immune system. TECs are divided into two specialized functionally distinct cortical (cTECs) and medullary (mTECs) subtypes, which derive from common bipotent TEC progenitors. Still, we know very little about the genetic basis that controls cTEC/mTEC lineage divergence from TEC progenitors. Interleukin-7 (IL-7) is a chief cytokine for T-cell development and a particular subtype of TECs produces it. We previously provided the first temporal-spatial analysis of thymic IL-7 niche in vivo. Over the last years, we have studied the development of IL-7-expressing TECs relatively to the establishment of mature thymic epithelial microenvironments. Future research goals 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: - Identify TEC progenitors and their niches within the fetal and adult thymus. - Examine the contribution of distinct TEC subsets to support T-cell development. - Elucidate the molecular basis that control cTEC/mTEC fate decisions. - Study the role of the thymus in pathophysiological states. Ultimately, as T-cell immune reconstitution relies on the bi-directional interplay between T-cell precursors and TECs, understanding the development and function of TECs is crucial to comprehend how the immune system achieves the equilibrium between immunity and tolerance. Selected References: Ribeiro AR, Meireles C, Rodrigues PM, Alves NL (2014) The intermediate expression of CCRL1 reveals novel subpopulations of medullary thymic epithelial cells that emerge in the postnatal thymus. Eur J Immunol. 2014 Jul 28 [Epub ahead of print] Alves NL, Takahama Y, Ohigashi Y, Ribeiro A, Baik S, Anderson G, Jenkinson WE (2014) Serial progression of cortical and medullary thymic epithelial microenvironments. Eur J Immunol. 44:16-22. Ribeiro AR, Rodrigues P, Meireles C, Di Santo JP, Alves NL (2013). Thymocyte selection regulates the homeostasis of IL-7-expressing thymic cortical epithelial cells in vivo. J Immunol.191:1200-9. Alves NL, Huntington ND, Mention JJ, Goff OR and Di Santo JP (2010) Cutting Edge: A thymocyte-thymic epithelial cell crosstalk dynamically regulates intrathymic IL-7 expression in vivo. J Immunol. 184: 5949-53. Alves NL, Huntington ND, Rodewald HR and Di Santo JP (2009) Thymic epithelial cells: the multi-tasking framework of the T cell "cradle". Trends Immunol .30 468-74. Alves NL, Goff OR, Huntington ND, Sousa AP, Ribeiro VS, Bordack A, Vives FL, Peduto L, Chidgey A, Cumano A, Boyd R, Eberl G, Di Santo JP (2009). Characterization of the thymic IL-7 niche in vivo. PNAS. 106:1512-1517.

Thymus Development and Function