Genetic regulation of thymocyte progenitor aging

Abstract

The number of T cell progenitors is significantly reduced in the involuted thymus, and the growth and developmental potential of the few cells that are present is severely attenuated. This review provides an overview of how aging affects T cell precursors before and following entry into the thymus and discusses the age-related genetic changes that may occur in them. Finally, interventions that rejuvenate thymopoiesis in the elderly by targeting T cell progenitors are discussed.

Figure 1

T cell progenitors in the bone marrow and thymus. Hematopoietic stem cells (HSCs) in the bone marrow generate Multipotential Progenitors (MPP) capable of producing lymphoid and myeloid progeny. Lymphoid Primed Multipotential Progenitors (LMPP) have lost most myeloid and erythroid potential and are candidate thymus seeding cells as shown by the solid arrow. Early T Lineage Progenitors (ETP) are the most immature intrathymic progenitor and are defined by their lineage negative CD44^high CD25⁻ CD117⁺ phenotype. ETP then mature into double negative (DN) stages defined by differential expression of CD44 and/or CD25. DN4 cells express the T cell receptor at low levels and then mature into CD4⁺CD8⁺ double positive (DP) thymocytes from which CD4 or CD8 single positive (SP) thymocytes derive. Note that other cells in addition to LMPPs may under some circumstances seed the thymus. These could include HSCs, CLPs, and even CMPs. The latter cells have recently been demonstrated to have residual T cell potential.

Figure 2

Proposed changes in gene expression in aging ETP. Changes in expression of one or more DNA methyltransferases (DNMTs), as a result of cell intrinsic or extracellular influences, may cause epigenetic modifications that affect the expression of genes that regulate ETP growth, differentiation, and/or survival. Our preliminary data indicate that expression of p16^INK4a is increased in ETP with age and is a factor that contributes to their reduced proliferation. A complex network regulates expression of p16^INK4a in cells. For example, various factors that include Id1, Ets1, Ets2, Bmi1, and Hmga2 can suppress p16^INK4a expression. Hmga2 in turn is under control of multiple upstream factors that include Lin 28 and the Let-7b microRNA. The precise factors that regulate p16^INK4a expression in ETP have not been defined.