An Overview of the Intrathymic Intricacies of T Cell Development

Abstract

The generation of a functional and diverse repertoire of T cells occurs in the thymus from precursors arriving from the bone marrow. In this article, we introduce the various stages of mouse thymocyte development and highlight recent work using various in vivo, and, where appropriate, in vitro models of T cell development that led to discoveries in the regulation afforded by transcription factors and receptor–ligand signaling pathways in specifying, maintaining, and promoting the T cell lineage and the production of T cells. This review also discusses the role of the thymic microenvironment in providing a niche for the successful development of T cells. In particular, we focus on advances in Notch signaling and developments in Notch ligand interactions in this process.

Prolongevity hormone FGF21 protects against immune senescence by delaying age-related thymic involution

“…Thymic involution likely occurs as a consequence of both intrinsic defects in thymocyte progenitors and a failure to maintain a functional TEC compartment (5)(6)(7)41). Aging reduces the number of TECs with a concomitant increase in lipid-laden cells, fibroblasts, and adipocytes (8,9,11).…”

“…As human lifespan continues to increase, it has been hypothesized that the ability to retain a functional level of thymic lymphopoiesis beyond the time limit set by evolutionary pressures may be an important strategy to extend healthspan (3,4). Therefore, the ability to enhance thymic lymphopoiesis is thought to be central to the rejuvenation of T-cell-mediated immune surveillance in the elderly (1)(2)(3)(4)(5)(6)(7). Aging is associated with marked perturbations in the stromal cell microenvironment of the thymus (8,9).…”

Pre-TCR ligand binding impacts thymocyte development before αβTCR expression

“…The earliest progenitors enter at the corticomedullary junction as CD4−CD8− [double-negative (DN)] CD44+CD25− (DN1) cells, extensively proliferate, and consecutively progress through DN2 (CD4−CD8−CD44+CD25+), DN3 (CD4−CD8−CD44−CD25+), and DN4 (CD4−CD8−CD44−CD25−) stages in the outer cortex before becoming CD4+CD8+ doublepositive (DP) cortical thymocytes, where proliferation is largely curtailed (1,2). T-cell receptor-β (TCRβ) gene locus rearrangement and expression first occur at the DN3 stage, whereas those of the TCRα locus follow at the DP stage.…”

Papel de la vía de señalización Notch en la diferenciación de las células inmunes

“…Esta interacción permite la activación de la vía de señalización Notch 1 que evita que estas células linfoides inmaduras pueda diferenciarse en células dendríticas (DC), en linfocitos B o en células mieloides (4); además, la activación de esta vía de señalización es crítica para que las células linfoides doblemente negativas puedan sobrevivir al proceso de β-selección, ya que Notch tiene una mayor actividad sobre las células T que expresan cadenas alfa (α) y beta (β), las cuales presentan el pre-receptor de las célula T (TBR) (10,11), que debe ser reconocido en esta etapa de selección negativa para que se continúe con el proceso de diferenciación celular. folicular madura.…”