Transcription Control of Immune Cell Fates
Oct2 enhances antibody secreting cell differentiation through regulation of IL5 receptor α chain expression on activated B cells
D Emslie, K D’Costa, J Hasbold, PD Hodgkin, LM Corcoran in collaboration with D Metcalf (Cancer and Haematology Division), K Takatsu (Department of Microbiology and Immunology, The Institute of Medical Science, University of Tokyo) Pub ref: 45
Mice lacking a functional gene for the Oct2 transcriptional activator display a number of developmental and functional deficiencies in the B lymphocyte lineage. These include defective B cell receptor (BCR) and toll-like receptor 4 (TLR4) signalling, an absence of B-1 and marginal zone populations, and globally reduced levels of serum immunoglobulin (Ig) in naïve and immunised animals. Oct2 was first identified through its ability to bind to regulatory regions in the Ig gene loci, but genetic evidence has not supported an essential role for Oct2 in expression of Ig genes. We have now found a new role for Oct2 in B cells. Oct2 augments the ability of activated B cells to differentiate to antibody-secreting plasma cells (ASC) under T cell-dependent conditions, through direct regulation of the gene encoding the α chain of the receptor for the cytokine IL5.
IL5 acts to augment ASC differentiation, and we show that this cytokine directly activates the plasma cell differentiation program by enhancing Blimp1 expression. Ectopic expression of IL5Rα in Oct2-deficient B cells largely restores their ability to differentiate to functional ASC in vitro, but does not correct other phenotypic defects in the mutants, such as the maturation and specialisation of peripheral B cells, which therefore must rely on distinct Oct2 target genes.
A model for the specific impact of extrinsic signals on the intrinsic regulation of T-dependent (TD) ASC differentiation. The phenotype and behavior of germinal center B cells is maintained through the repressive activities of Bcl6, Bach2, and Pax5. Upon immune activation, antigen can signal Bcl6 degradation, and T cells, through CD40, can magnify this effect by activating IRF4, a repressor of Bcl6 transcription. T cell-derived cytokines, such as IL-4 and IL-5, combine to activate Blimp1 transcription. Pax5 protein activity is down-modulated by an unknown mechanism. Once Blimp1 and IRF4 reach sufficiently high levels (and Bcl6, Pax5, and Bach2 levels have been reduced), the ASC program is reinforced by unopposed repression of Bcl6, Pax5, and Bach2 by the plasma cell determinants IRF4 and Blimp1.
The role of the transcription factor Blimp1 in effector and memory T cell differentiation
A Kallies, GT Belz, A Xin, SL Nutt in collaboration with J Curtis, E Handman (Infection and Immunity Division) Pub ref: 108, 177, 207
The acquisition of effector functions is a hallmark of the terminal lymphocyte differentiation. The B lymphocyte induced maturation protein 1, Blimp1, is a transcription factor whose importance in differentiation of antibody secreting cells is well established. Its role in T cells, however, is less understood. In order to examine the role of Blimp1 in T cell differentiation and function in vivo we use mice chimeric for Blimp1-deficient and wild-type T cells in two different infection models, a viral (influenza) and a parasitic (Leishmania major) infection. Our findings suggest that Blimp1 is crucial for the control of effector T cell differentiation during an immune response and for the function of memory T cells.
Dr Phil Hodgkin delivered a public lecture on the immune system at the Irish Academy, Dublin in July 2007. The event was part of a Walton travelling Fellowship and sponsored by the Australian Embassy and the Science Foundation Ireland. Here Phil Hodgkin discusses the lecture with Her Excellency Anne Plunkett the Australian Ambassador to Ireland and the Holy See, and Professor Peter Wellstead Head of Systems Biology at the Hamilton Institute in Maynooth.
Identification of Pax5 target genes in early B cell differentiation
C Pridans, ML Holmes, LM Corcoran, SL Nutt, in collaboration with JM Wettenhall, GK Smyth (Bioinformatics Division) Pub ref: 114
The transcription factor Pax5 is essential for B cell commitment in the mouse, where it represses lineage-inappropriate gene expression, while simultaneously activating the B cell gene expression program. In an attempt to identify the crucial targets of Pax5, we have performed a global gene expression screen of wild type and Pax5-deficient pro-B cells. These studies have identified 109 Pax5 targets, comprising 61% activated and 39% repressed genes. Interestingly, Pax5 directly regulates the genes encoding a number of components of the pre-B cell receptor (pre-BCR) complex and its downstream signal transduction pathway. Another key function of Pax5 is to activate secondary transcription factors, including Irf8, Spib and Aiolos, which further reinforce the B cell program. Pax5 is also required for the expression of many genes known to be involved in adhesion and signalling, indicating that Pax5 modulates the homing and or migration properties of B cell progenitors. Finally Pax5 also represses a cohort of genes that are involved in multiple biological processes, many of which are not typically associated with B cells. This includes the repression of the adhesion molecule Embigin, which is expressed in bone marrow progenitors, T cells and myeloid cells, but specifically repressed by Pax5 in B cells.