ReviewMolecular and cellular basis of T cell lineage commitment
Introduction
During embryogenesis, the generation of the prospective thymic epithelium in the third pharyngeal pouch endoderm and the vascularisation of the resulting thymus anlagen is dependent upon the activity of the Foxn1 transcription factor [1], [2]. The expansion and maturation of this embryonic thymic epithelium is regulated by neural crest-derived mesenchyme [3]. Immigration of the first T precursors occurs only upon proper fabrication of this thymic anlage; their differentiation within the thymus results in the establishment and maintenance of a mature peripheral T cell pool with a wide self-MHC-restricted non-autoimmune TCR repertoire.
The crucial role of the thymus in T cell generation was demonstrated by seminal studies conducted by the Australian scientist Francis Albert Pierre Miller [4]. The thymus was already acknowledged by the Greeks and its name may be derived from the Greek word “thymos” which denoted life force or soul. Despite this rich history and even though Miller's pioneering work on the thymus was performed in 1961, it was long thought that the thymus was obsolete with its function having become redundant during the course of evolution. Indeed, in 1963, Sir Peter Medawar, recipient of the 1960 Nobel prize for his work on graft rejection and the acquisition of immune tolerance, stated; “We shall come to regard the presence of lymphocytes in the thymus as an evolutionary accident of no very great significance” (Medawar, 1963) [5]. During the past half century, remarkable progress has been made, and it is no longer possible to study T cell development without recognizing the critical importance of the thymus in this process.
At what point in its development does a hematopoietic precursor cell become destined to pursue a T lineage fate? The phenotype and characteristics of hematopoietic progenitors have been extensively studied during the past decade, resulting in the identification of multiple bone marrow and peripheral blood subsets that are capable of differentiating into T lineage cells in the thymus. Despite enormous advances in the field, there are still considerable issues that remain unresolved. The phenotypes of hematopoietic precursor cells in mice and humans differ significantly, adding yet another layer of complexity to research aimed at understanding the regulation of T lineage commitment. Further complexities are the result of recent findings showing that the destinies of apparently identical hematopoietic precursors differ based on the milieu in which they are localized; i.e. bone marrow versus thymus. Here, we review recent findings arising from studies of hematopoietic precursor phenotypes in mice and humans, regulation of thymocyte differentiation and thymic importation of hematopoietic precursors.
Section snippets
Thymocyte differentiation: which cells are competent to pursue a T lineage fate?
In the murine thymus, the immature early T lineage progenitor (ETP) has high T and only limited B potential [6]. These thymocyte precursors, characterized as lin−CD44+CD25−Sca-1+c-kit+ (LSK) with only low CD127 (IL-7Rα) expression, are derived from hematopoietic stem cells (HSC) in the bone marrow. However, HSC themselves do not appear capable of seeding the thymus under physiological conditions. The most immature progenitors in the thymus do not harbor stem cell potential as shown by their
Of mice and men: phenotypes of human thymocyte precursors and subsets
In humans, the phenotype of the primitive hematopoietic precursor capable of giving rise to differentiated lineages is distinct from that detected in mice. In contrast to the lin−Sca-1+c-kit+ (LSK) progenitors found in mice, human hematopoietic precursors harbor the CD34 marker. The CD34+ cells that seed the thymus can differentiate into multiple lineages, giving rise not only to T, B and NK cells of the lymphoid compartment but also to myeloid cells such as DCs and erythrocytes [25], [26]. T
Of mice and men: Notch and IL-7
Within the thymic microenvironment, the interplay between the Notch1 transcription factor and the IL-7 cytokine is crucial in supporting and orchestrating T cell development. However, the precise requirements for these factors in murine and human thympoeisis, as monitored by differentiation and proliferation, are not synonymous. The role of Notch1 in commitment to the T cell lineage was elegantly demonstrated by two ground-breaking studies showing that a constitutively active Notch1 results in
Getting in: regulating access of hematopoietic precursors to the thymus
Irrespective of the precise nature of the cell(s) gaining access to the thymus (see Section 2), it is important to understand the processes regulating the migration and colonization of these hematopoietic progenitors. The murine thymus is apparently not continually receptive to the import of hematopoietic progenitors, alternating between refractory and responsive periods [62]. During refractory periods, donor progenitor cells differentiate into T cells only if they are directly injected into
Forcing entry of progenitors into the thymus: long-term thymopoiesis
The concept that the early thymic precursors (characterized as CD44+CD25−Sca-1+c-kit+) are the source for all subsequent thymocyte differentiation is widely accepted, but this has not been formally proven. It is clear that the thymic environment can modulate the function and phenotype of precursors. While BM HSC and ETP share many phenotypic markers, only the latter are dependent on Notch signals for their generation and maintenance [42], [43]. Moreover, exposure of bone marrow-derived CLP to a
Acknowledgments
We thank all members of our lab for their scientific critique and support and are grateful to Valérie Dardalhon for discussion and critical reading of the manuscript. We are indebted to Al Singer for his gracious exchange of ideas on human and murine T cell differentiation. R.V. was supported by a fellowship from the Portuguese Foundation for Science and Technology (SFRH/BD/23553/2005) and L.S. by the ANRS and Sidaction. Funding was provided by grant R01AI059349 from the National Institute of
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