REVIEW The long road to the thymus: the generation, mobilization, and circulation of T-cell progenitors in mouse and man Daniel A. Zlotoff & Benjamin A. Schwarz & Avinash Bhandoola Received: 7 August 2008 / Accepted: 30 September 2008 / Published online: 17 October 2008 # Springer-Verlag 2008 Abstract The majority of T cells develop in the thymus. T- cell progenitors in the thymus do not self-renew and so progenitor cells must be continuously imported from the blood into the thymus to maintain T-cell production. Recent work has shed light on both the identity of the cells that home to the thymus and the molecular mechanisms involved. This review will discuss the cells in the bone marrow and blood that are involved in early thymopoiesis in mouse and man. Understanding the pre-thymic steps in T-cell develop- ment may translate into new therapeutics, especially in the field of hematopoietic stem cell transplantation. Keywords Hematopoietic stem cells . Hematopoietic progenitors . Mobilization . Thymic settling . Early thymic progenitors Introduction T cells are critical mediators of the adaptive immune response. T-lineage cells include CD4 + T-helper cells, CD8 + cytotoxic T cells, and FoxP3 + regulatory T cells (Tregs), and are important for immunity and self-tolerance. The spread of HIV, which infects CD4 + T cells, has further demonstrated the importance of T-cell-mediated immunity to bacteria, viruses, and fungi. As knowledge of T-cell functions has grown, so has interest in the origins of T cells. Like all blood lineages, T cells are derived from hemato- poietic stem cells (HSCs) that reside in the bone marrow (BM) [1]. Unlike other blood lineages, however, T cells complete the majority of their development in a specialized organ in the mediastinum—the thymus [2]. The thymic stroma perform several key functions in T-cell develop- ment, including imposing a T-cell fate on arriving progen- itors and regulating the repertoire of T-cell receptors [3, 4]. The intrathymic developmental pathway ultimately produ- ces naïve T cells, which then emigrate from the thymus to populate the periphery. Understanding T-cell development has many potential clinical implications for T-cell reconstitution. This is important in several scenarios in which people can lose a significant proportion of T cells. Examples include the rare number of patients born with genetic T-cell deficiencies, and, more commonly, patients with acquired T-cells deficiencies such as HIV/AIDS or T-cell deficiency following stem cell transplantation (SCT) [5–7]. Addition- ally, thymic output falls with normal aging [8]. In such situations, the protection that T cells offer is partially or completely lost. The identification of the cells that settle in the thymus, and the mechanisms by which they do so, could conceivably help clinicians rapidly and efficiently restore the T-cell compartment. This might greatly reduce the dangers of SCT, for example, by substantially diminish- ing the immunosuppression that normally accompanies this treatment [9, 10]. HSCs are the ultimate source of T cells. They reside mainly within specialized niches in the BM, though some HSCs can be found in blood and extramedullary sites [11]. The thymus does not contain self-renewing progenitors (such as HSCs) and therefore must import progenitors Semin Immunopathol (2008) 30:371–382 DOI 10.1007/s00281-008-0133-4 D. A. Zlotoff : A. Bhandoola (*) Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, 264 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA, USA e-mail: bhandooa@mail.med.upenn.edu B. A. Schwarz Department of Pathology, Massachusetts General Hospital, Boston, MA, USA