Eliciting the T cell fate with Notch

Abstract

Multipotent progenitors arrive at the thymus via the blood. Constraining the non-T cell fates of these progenitors while promoting the T cell fate is a major task of the thymus. Notch appears to be the initial trigger for a developmental program that eventually results in T cell lineage commitment. Several downstream targets of Notch are known, but the specific roles of each are poorly understood. A greater understanding of how Notch and other thymic signals direct progenitors to a T cell fate could be useful for translational work. For example, such work could eventually allow for the generation of fully competent T cells in vitro that could supplement the waning T cell numbers and function in the elderly and boost T cell-mediated immunity in patients with immunodeficiency and after stem cell transplantation.

Fig. 1. Cellular substrates and molecular signals in T cell development

Within the bone marrow, hematopoietic stem cells (HSCs) differentiate into multipotential progenitors (MPPs). A subset of MPPs that are Flt3^hi termed lymphoid-primed multipotential progenitors (LMPPs). HSCs, MPPs and LMPPs have the Lin⁻Sca-1^hic-Kit^hi (LSK) phenotype. Subsequent progenitors include common lymphoid progenitors (CLPs). Both LMPPs and CLP express CCR7 and high level of Notch1. All of the bone marrow progenitors express PSGL-1 and circulate in the blood. Circulating T cell progenitors (CTPs) have also been identified in blood and are candidate T cell progenitors. CTP may feed directly to downstream stages of thymocytes development without going through an ETP to DN2 stage. The ability of circulating progenitors to settle within the thymus is regulated and requires the molecules chemokine receptor CCR9, CCR7 and P-selectin glycoprotein ligand-1 (PSGL-1). Thymus settling progenitors generate Flt3⁺ Early thymic progenitors (ETPs) and Flt3^lo ETPs. Double-Negative 2 (DN2), Double-Negative 3 (DN3) cells arise from ETPs. T cell commitment through these stages (ETP to DN3) depends on a set of regulators include both T-cell specific and shared transcription factors and signaling molecules. "Lin" refers to a lineage cocktail containing a mixture of antibodies to surface antigens expressed by differentiated cell types and contains antibodies to CD8α, CD8β, TCRβ, TCRγ, CD3ε, NK1.1, Mac1 (CD11b), Gr1, B220, CD19, CD11c, and Ter119.