The intrathymic crossroads of T and NK cell differentiation
ABSTRACT T lymphocytes depend on the thymic microenvironment for initiation of the T-cell developmental program. As the progenitors in the thymus have lost the capacity to self-renew, this process depends on the constant influx of hematopoietic progenitors that originate in the bone marrow. Nevertheless, thymic emigrants are heterogeneous and retain developmental plasticity for both the myeloid and lymphoid lineages. It is the role of the thymic microenvironment to steer these uncommitted progenitors toward a T-cell fate. Still, the thymus also generates a unique population of thymic NK cells, thus raising the question of how the T versus NK lymphoid cell fate is determined intrathymically. Many factors have been implicated in the developmental pathways in the thymus, and the processes are characterized by both subtle and not so subtle modifications in gene expression. In this review, we consider the crucial factors governing lineage determination of T cells versus NK cells from bi-potent thymic NK/T precursors. Recent reports have shed new light on the complex interactions of cytokines and transcription factors at different cell fate decision branch points in thymopoiesis. We discuss the implications of these findings and propose a model that may be applicable at this critical thymic NK/T juncture.
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ABSTRACT: T-cell development from stem cells has provided a highly accessible and detailed view of the regulatory processes that can go into the choice of a cell fate in a postembryonic, stem cell-based system. But it has been a view from the outside. The problems in understanding the regulatory basis for this lineage choice begin with the fact that too many transcription factors are needed to provide crucial input: without any one of them, T-cell development fails. Furthermore, almost all the factors known to provide crucial functions during the climax of T-lineage commitment itself are also vital for earlier functions that establish the pool of multilineage precursors that would normally feed into the T-cell specification process. When the regulatory genes that encode them are mutated, the confounding effects on earlier stages make it difficult to dissect T-cell specification genetically. Yet both the positive and the negative regulatory events involved in the choice of a T-cell fate are actually a mosaic of distinct functions. New evidence has emerged recently that finally provides a way to separate the major components that fit together to drive this process. Here, we review insights into T-cell specification and commitment that emerge from a combination of molecular, cellular, and systems biology approaches. The results reveal the regulatory structure underlying this lineage decision.Immunological Reviews 11/2010; 238(1):150-68. DOI:10.1111/j.1600-065X.2010.00964.x · 12.91 Impact Factor
- Immunological Reviews 11/2010; 238(1):5-11. DOI:10.1111/j.1600-065X.2010.00965.x · 12.91 Impact Factor
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ABSTRACT: NK cells are components of the innate immunity system and play an important role as a first-line defense mechanism against viral infections and in tumor immune surveillance. Their development and their functional activities are controlled by several factors among which cytokines sharing the usage of the common cytokine-receptor gamma chain play a pivotal role. In particular, IL-2, IL-7, IL-15, and IL-21 are the members of this family predominantly involved in NK cell biology. In this paper, we will address their role in NK cell ontogeny, regulation of functional activities, development of specialized cell subsets, and acquisition of memory-like functions. Finally, the potential application of these cytokines as recombinant molecules to NK cell-based immunotherapy approaches will be discussed.BioMed Research International 06/2011; 2011(1110-7243):861920. DOI:10.1155/2011/861920 · 2.71 Impact Factor