Life and death in the thymus—cell death signaling during T cell development

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The thymus is an organ vital to proper T cell development, and the regulation of cell survival and death contributes significantly to its efficient function. Vital to many of the developmental processes that occur in the thymus, control over cell survival and death is orchestrated by several signaling processes. In this review, we focus on the regulation of death in early thymocytes known as CD4/CD8 double negative cells, including the roles of interleukin-7 and Bcl-2 family members in this developmental stage. We next consider the survival and death of later thymocytes that express both CD4 and CD8, the ‘double-positive’ thymocytes. These findings are discussed within the context of recent studies demonstrating the existence of caspase-independent cell death pathways.

Introduction

Among the first cell types to be characterized as undergoing steady state cell death, thymocytes offer valuable insight into the regulation of organ system development and tissue homeostasis. The thymus itself directs the process of early T cell differentiation, and a number of developmental stages depend on life vs. death choices that are intricately programmed. Perhaps unique to the genesis of lymphocytes, the essentially stochastic process involved in the rearrangement of T and B cell antigen receptor genes requires subsequent selective mechanisms that ensure that antigen receptors are minimally functional without being autoreactive. Indeed, the deletion of autoreactive lymphocytes is one of the key means by which ‘immunological tolerance,’ the prevention of autoreactivity, is achieved. This elimination of autoreactive lymphocytes during their development is termed ‘central tolerance,’ and is the primary means of elimination of lymphocytes that would otherwise potentiate autoimmune disease. Programmed mechanisms that modulate cell survival vs. cell death are essential for many of these selective processes. Once functional lymphocytes are produced and released to the periphery, additional cell death mechanisms control lymphoid homeostasis, and provide a secondary layer of self-tolerance termed ‘peripheral tolerance.’ Our focus in this review is specifically directed toward the cell death processes that occur within the thymus. For those interested in peripheral tolerance and lymphoid homeostasis, the reader is directed to other reviews on the subject.

Section snippets

Survival and death of early thymocytes, the ‘double-negative’ sub-populations

A thymocyte is first generated from the interaction of a hematopoietic stem cell with a thymic stromal cell. In order for a thymocyte to differentiate into a mature T lymphocyte it must go through maturational stages. The first stage is termed the double negative (DN) stage because thymocytes in this stage lack the CD4 or CD8 co-receptors. The double negative stage can be broken down even further into four successive developmental subsets based on the cell surface expression of the CD117, CD44,

Death at the CD4/CD8 double positive developmental stage of thymopoiesis

During the DN4 precursor stage of thymocyte development, TCR α chain rearrangement ensues, resulting in the display of a fully assembled TCR. As thymocytes transit to the double positive (DP) stage, these thymocytes enter a period of quiescence that lasts an average of three to four days. Several survival factors are expressed that allow the opportunity to test the newly displayed TCR. This ‘TCR selection’ is imperative, as it will lead to three potential fates as dictated by the strength of

Conclusions

The thymus is an essential organ system that is imbued with the significant task of orchestrating the development of functional T cells, and the prevention of systemic autoimmunity. As described in this review, the proper regulation of cell death is vital to the function of the thymus. Although the function of the thymus wanes as humans reach adulthood, it remains active throughout one's lifetime. The intricate control over myriad cell survival and death processes in the thymus underscores the

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements:

This work was supported by grants from the NIH (CMW: R01 AI63419, AI50506; RHN: immunology training grant T32-AI60573), the National Multiple Sclerosis Foundation, the Arthritis National Research Foundation, and the Juvenile Diabetes Research Foundation.

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