Evidence implicating Gfi-1 and Pim-1 in pre-T-cell differentiation steps associated with β-selection

Abstract

After rearrangement of the T-cell receptor (TCR)β-locus, early CD4 -/CD8 -double negative (DN) thymic T-cells undergo a process termed 'β-selection' that allows the preferential expansion of cells with a functional TCR β-chain. This process leads to the formation of a rapidly cycling subset of DN cells that subsequently develop into CD4 ϩ /CD8 ϩ double positive (DP) cells. Using transgenic mice that constitutively express the zinc finger protein Gfi-1 and the serine/threonine kinase Pim-1, we found that the levels of both proteins are important for the correct development of DP cells from DN precursors at the stage where 'β-selection' occurs. Analysis of the CD25 ϩ /CD44 -,lo DN subpopulation from these animals revealed that Gfi-1 inhibits and Pim-1 promotes the development of larger β-selected cycling cells ('L subset') from smaller resting cells ('E subset') within this subpopulation. We conclude from our data that both proteins, Pim-1 and Gfi-1, participate in the regulation of β-selection-associated pre-T-cell differentiation in opposite directions and that the ratio of both proteins is important for pre-T-cells to pass the 'E' to 'L' transition correctly during β-selection.

Targets of the transcriptional repressor oncoprotein Gfi-1

“…Induction of Gfi-1 by IL-4 increases Th2 cell expansion by promoting proliferation and preventing apoptosis (10). Gfi-1 cooperates with the cell-cycle regulators PIM-1 and cMyc (6,7,40). The E2F family of transcription factors also plays a critical role in cell-cycle progression through its ability to regulate the expression of target genes, including cyclins and cyclin-dependent kinases (41).…”

G1/S transcriptional networks modulated by the HOX11/TLX1 oncogene of T-cell acute lymphoblastic leukemia

“…Among these are Socs-1, which functions at the transition from the CD25 þ CD44 À double-negative thymocyte stage to the CD4 þ CD8 þ double-positive stage stage (Fujimoto et al, 2000;Trop et al, 2001), and the oncogenic Tcell transcription factor Gfi-1 (Schmidt et al, 1998a), which is similarly required at this stage (Schmidt et al, 1998b) and which has been reported to predispose to Tcell tumorigenesis by promoting S-phase entry concomitant with hyperphosphorylation of Rb (Karsunky et al, 2002).…”

Pim serine/threonine kinases regulate the stability of Socs-1 protein

“…Both Pim-1 and Pim-2 have been implicated in thymocyte development (17,27). Forced expression of Pim-1 rescues the defects in thymocyte development caused by deficiency in RAG, IL-7, or the common ␥-chain of cytokine receptors (17).…”