Tomonori Hosoya From the cradle to the grave: Ivan Maillard activities of GATA-3 throughout James D. Engel T-cell development and differentiation
Authors’ addresses Summary: GATA family transcription factors play multiple vital roles in 1 1,2,3 1 Tomonori Hosoya , Ivan Maillard , James D. Engel hematopoiesis in many cell lineages, and in particular, T cells require 1 Department of Cell and Developmental Biology, University GATA-3 for execution of several developmental steps. Transcriptional of Michigan Medical School, Ann Arbor, MI, USA. activation of the Gata3 gene is observed throughout T-cell development 2 Division of Hematology ⁄ Oncology, Department of and differentiation in a stage-specific fashion. GATA-3 has been described Internal Medicine, University of Michigan Medical School, as a master regulator of T-helper 2 (Th2) cell differentiation in mature Ann Arbor, MI, USA. CD4+ T cells. During T-cell development in the thymus, its roles in the 3 Center for Stem Cell Biology, Life Sciences Institute, CD4 versus CD8 lineage choice and at the b-selection checkpoint are the University of Michigan, Ann Arbor, MI, USA. best characterized. In contrast, its importance prior to b-selection has been obscured both by the developmental heterogeneity of double nega- Correspondence to: tive (DN) 1 thymocytes and the paucity of early T-lineage progenitors James D. Engel (ETPs), a subpopulation of DN1 cells that contains the most immature 109 Zina Pitcher Place, 3072 BSRB thymic progenitors that retain potent T-lineage developmental potential. Ann Arbor, MI 48109, USA By examining multiple lines of in vivo evidence procured through the Tel.: +1 734 615 7509 analysis of Gata3 mutant mice, we have recently demonstrated that GATA- Fax: +1 734 615 8500 3 is additionally required at the earliest stage of thymopoiesis for the e-mail: [email protected] development of the ETP population. Here, we review the characterized functions of GATA-3 at each stage of T-cell development and discuss Acknowledgements hypothetical molecular pathways that mediate these functions. T. H. was supported in part by a fellowship from the Astellas Foundation for Research on Metabolic Disorders. I. M. was Keywords: GATA-3, ETP, b-selection, CD4 SP, Th2 supported by the Damon Runyon Cancer Research Foundation and the American Society of Hematology. This research was initially supported by National Institutes of Health research grant R01 GM28896 to J. D. E. T-cell development in thymus T-cell production in the thymus is supported by continuous, life-long migration of T-cell progenitors derived from hema- topoietic stem cells (HSCs) in the bone marrow (1). Most if not all current models for lineage specification from HSCs derive from the concept that, as cells mature, they progres- sively lose more and more differentiation potential (Fig. 1). HSC and multi-potential progenitors (MPPs) reside in the phe- ) ) notypically defined LSK [lineage (Lin )Sca1+cKithi] popula- Immunological Reviews 2010 tion (Table 1), and early developmental induction of cell Vol. 238: 110–125 Printed in Singapore. All rights reserved surface fms-like tyrosine kinase 3 (Flt3) expression within this population is accompanied by a loss of self-renewal 2010 John Wiley & Sons A/S Immunological Reviews potential (2, 3). In comparison to MPPs, lymphoid-primed 0105-2896 MPPs (LMPPs) have markedly reduced erythroid potential
110 2010 John Wiley & Sons A/S • Immunological Reviews 238/2010 Hosoya et al Æ GATA-3 regulates multiple stages of T-cell development
Early Intermediate Late
Thymus homing T-lineage commitment Positive selection Loss of B-cell potential β-selection CD4 versus CD8 choice T-lineage specification Negative selection
HSC HSC
E MPP MPP ? CD4 M LMPP ? TSP ETP DN2 DN3 DN4 DP SP
γδ CD8 CLP CLP T SP
proB Fr.A ?
B CTP
Bone marrow Blood Thymus
Fig. 1. A model for T lymphopoiesis. Popular models for lineage specification from HSCs derive from the concept that, as cells mature, they progres- sively lose differentiation potential. Myeloid, B and T-lineage potential are shown in orange, blue, and green, respectively. Cells that are committed to the T lineage are shown in dark green. The identity of the thymus homing cells remains controversial. Possible homing cells are shown in dashed lines. GATA-3 is required for the development of ETP, DN4, and CD4 SP T cells in the thymus (magenta arrow). E, erythroid lineage cells; M, myeloid line- age cells; B, B lymphoid lineage cells.
Table 1. Hematopoietic populations and abbreviations (mouse) Cell population Abbreviation Cell surface phenotype ) Lineage negative cells Lin ) LSK Lin Sca1+cKithi ) ) ) Hematopoietic stem cell HSC CD150+CD48 CD34 Flt3 LSK Multipotent progenitors MPP Flt3loLSK Lymphoid-primed multipotent progenitors LMPP Flt3hiLSK ) Common lymphoid progenitors CLP Lin IL7Ra+Sca1locKitlo ) ) ) ) ) ) ) Early thymic progenitors ETP CD8 CD3 TCRb cdTCR NK1.1 CD11c Mac1 ) ) ) ) ) Gr1 B220 CD19 Ter119 cKithiCD25 ) ) ) Double negative T cells, stage 1 DN1 CD4 CD8 CD44+CD25 ) ) Double negative T cells, stage 2 DN2 Either Lin cKithiCD25+ or Lin CD44+CD25+ ) ) ) ) Double negative T cells, stage 3 DN3 Either Lin cKitlo ⁄ CD25+ or Lin CD44 CD25+ ) ) ) ) ) ) Double negative T cells, stage 4 DN4 Either Lin cKitlo ⁄ CD25 or Lin CD44 CD25 Double positive DP CD4+CD8+ ) ) Single positive SP Either CD4+CD8 or CD4 CD8+
(4–7). While most hematopoietic lineage cells (specifically Sca1loIL7Ra+ [common lymphoid progenitor (CLP)] (20, ) erythroid, myeloid, and B lymphoid cells and all of their 21), and in the B220+ CD19 population (22, 23). Regardless progenitors) develop in the fetal liver and ⁄ or bone marrow, of their cellular origin, very rare (and at this point, hypotheti- T lymphoid cells develop in the thymus, which provides cal) thymus-seeding progenitors (TSPs) upon encountering unique microenvironmental cues that are essential for T-cell the thymic epithelium are thought to amplify to generate early development (8). T-lineage progenitors (ETPs), the most immature T-cell pro- T-lymphocyte progenitors migrate into the thymus from the genitors in the thymus that have been characterized (24–26). ) fetal liver or bone marrow through the blood stream. Chemo- Intrathymic ETPs constitute a cKithiLin fraction that har- kines, cell adhesion molecules, and their receptors bors all of the most potent T-cell developmental potential but CCL25 ⁄ CCR9, CCL19-CCL21 ⁄ CCR7, and P-selectin ⁄ PSGL-1 comprises only a subset of about 2–4% of all double negative regulate this migration (9–15). The identity of thymus-hom- 1 (DN1) stage cells (27). Very shortly after thymic entry, ing cells continues to be controversial (reviewed in 16). These these progenitors lose their B-cell potential and become speci- cells have been proposed to reside in several different bone fied to the T-cell lineage. The most immature subset (Flt3+)of marrow compartments that are distinguishable by their expres- adult ETPs retains modest B-cell developmental potential (27, ) sion of different cell surface markers: LSK (17–19), Lin cKitlo 28). Thymic epithelial cells express the Notch ligand Delta-