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Molecular Genetics of B- and T Lymphocyte Development

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Molecular Genetics of B- and T Lymphocyte Development UMEÅ UNIVERSITY MEDICAL DISSERTATIONS New series no.1030, ISSN 0346-6612, ISBN 91-7264-089-8 Molecular Genetics of B- and T Lymphocyte Development Ingela Wikström Department of Medical Biosciences Unit of Medical and Clinical Genetics Umeå University Sweden 2006 Department of Medical Biosciences Unit of Medical and Clinical Genetics Umeå University SE-901 85 Umeå, Sweden Copyright © 2006 by Ingela Wikström ISSN 0346-6612 ISBN 91-7264-089-8 Printed by Solfjädern Offset AB in Umeå, Sweden, 2006 2 Table of contents Abstract………….……………………………………………………………......................5 Abbreviations………………………………...……………………………………………...6 Articles……………………………………………………………………...……….………7 Introduction…………………………………………………………………………………8 1.1 The immune system…………………………………………...………………………...8 The non-specific immune system………………………………………………………...8 The specific immune system……………………………………………………………..8 1.2 Function of lymphocytes………………………………………………………………..9 B lymphocytes…………………………………………………………………………....9 T lymphocytes…………………………………………………………………………..13 1.3 Lymphocyte development……………………………………………………………..17 B cell development………………………………………………………………….…..17 T cell development……………………………………………………………………...21 2.1 Transcription factors controlling lymphocyte development….…………………….25 2.2 Basic helix-loop-helix transcription factors………………………………………….27 Structure, function and subclasses of bHLH proteins…………………………………..28 Regulation of E-protein activity………………………………………………………...30 E-proteins in B cell development……………………………………………………….31 E-proteins in T cell development………………………………………………………..35 Signalling pathways regulating E-protein function…………………………………..…37 3 Aims of the study…………………………………………………………………….…….38 Results and discussion……………………………………………………………………..38 Paper I: The role of Dµ protein in B cell development…………………………...…38 Paper II: The role of E2-2 in B cell development………………………………...…42 Paper III: The role of E2-2 in T cell development……………………………..……45 Conclusions………………………………………………………………………………...49 Acknowledgements………………………………………………………………………...50 References………………………………………………………………………………….52 Articles and manuscripts………………………………………….....................................73 4 Abstract Lymphocytes are essential for the generation of specific immunity. Development of B cells in the bone marrow and T cells in the thymus have several analogous features, and are tightly regulated processes. Even though there is an increasing amount of information concerning lymphopoiesis, many questions remain unanswered. The aim of this thesis has been to understand some of the molecular events that contribute to the control of lymphocyte development. Expression of the B cell receptor is an important checkpoint in B lymphocyte development. The Dµ protein is a truncated B cell receptor that can induce some of the signals elicited by full length µ, but cannot promote further B cell differentiation. In order to determine if this could stem from an impaired survival signal, we introduced Bcl-2 into RAG2 deficient Dµ transgenic mice. Analysis of these mice showed that Dµ could not support pre-B cell maturation despite extended survival of B cell precursors by Bcl-2. In addition, data from recombination competent Dµ transgenic mice demonstrated that the Dµ induced partial block is permissive for marginal zone B cell development, whereas the formation of follicular B cells is severely reduced. The bHLH family of transcription factors is known to be involved in the regulation of lymphocyte development. Whereas the roles of E2A and HEB have been well documented in both B- and T-lymphocytes, detailed knowledge concerning E2-2 is lacking. To address the role of E2-2 in B cell development, we have reconstituted mice, using E2-2 deficient fetal liver cells, and analysed the B cell compartments. We also measured mRNA expression patterns for the three E- proteins in wildtype mice. Resulting data show that, in addition to a role in B cell lineage entry, E2- 2 is required for efficient expansion of pro-B cells, and also influences the follicular versus marginal zone decision. While focusing on assigning a role for E2-2 in T-cell development, we analyzed the expression of the E-proteins during this process and performed functional studies in fetal thymic organ cultures. E2-2 deficient mouse embryos were shown to display a partial block at the DN3 stage, which was not due to proliferation or apoptosis defects. In addition, analysis of expression levels of the pre-Tα chain suggests that E2-2 may play a role in the regulation of transcription of pre-Tα, and therefore in the assembly of the pre-T cell receptor. 5 Abbreviations APC antigen presenting cell BCR B cell receptor bHLH basic helix-loop-helix BM bone marrow C constant CTL cytotoxic T lymphocyte D diversity DC dendritic cell DN double negative DP double positive FL fetal liver H heavy Het heterozygous Ig immunoglobulin ISP immature single positive ITAM immunoreceptor tyrosine-based activation motif J joining KO knockout L light MHC major histocompatibility complex MZ marginal zone pBCR pre-B cell receptor pTCR pre-T cell receptor pTα pre-TCRα chain RAG recombination activating gene RF reading frame RSS recombination signal sequence SLC surrogate light chain SP single positive TCR T cell receptor TG transgene TH T helper lymphocyte V variable WT wildtype 6 Articles I. Wikström I., Bergqvist I., Holmberg D. and Forssell J. (2006) Dµ expression causes enrichment of MZ B cells, but is non permissive for B cell maturation in Rag2-/- mice even if combined with Bcl-2. Mol Immunol, 2006 Mar;43(9):1316-24 II. Wikström I.∗, Forssell J.∗, Penha-Goncalves M., Colucci F. and Holmberg D. E2-2 regulates the expansion of pro-B cells and follicular versus MZ decisions. Submitted April 2006 III. Wikström I., Penha-Goncalves M., Forssell J., Bergqvist I. and Holmberg D. A non- redundant role for the bHLH transcription factor E2-2 in early thymocyte development. Manuscript under revision in Eur J Immunol ∗ These authors contributed equally to this paper 7 Introduction 1.1 The immune system Each day we are challenged by potentially disease-causing microorganisms like viruses, bacteria, fungi and parasites. Luckily our body has developed a system designed to battle intruders that enter our blood or tissues; the immune system. One fundamental property of this system is that it can discriminate between self and non-self and therefore clear infections without causing too much damage to self-tissue. In vertebrates the immune system consists of both non-specific (innate) and specific (adaptive) components that are dependent on each other and work in close collaboration to rid the body of pathogens. The non-specific immune system is also called the innate immune system and is our first line of defence, immediately able to combat a wide range of pathogens without the need for prior exposure. The epithelial surfaces of the body are the first defence against infection, not only providing a physical barrier to infections but also producing antibacterial enzymes and peptides. Low pH and the normal flora of non-pathogenic bacteria are other obstacles that intruders must overcome in order to manifest an infection. Innate immunity also involves phagocytic cells, like macrophages and neutrophils that engulf and destroy microorganisms, as well as the complement system that recruits inflammatory cells, lyses pathogens or targets them for phagocytosis by other cells. Only if an infectious organism can break the early defence set up by the innate immune system will an adaptive immune response develop. The specific (adaptive) immune system does not become fully activated until several days after infection. It develops during the lifetime of an individual as an adaptation to infections and in many cases it confers lifelong immunity to re-infection from the same pathogen. The adaptive immune system involves antibodies against a specific pathogen, the humoral immune response, as well as the cell-mediated immune response, where infected cells are destroyed by T lymphocytes. These immune responses depend upon the clonal selection of lymphocytes. Each lymphocyte has a unique antigen receptor, generated by somatic gene rearrangements, that will scan the surroundings for pathogens. If a lymphocyte encounters 8 the antigen to which its receptor is specific, it will become activated, proliferate, and give rise to many cells with the same specificity. These antigen-specific effector lymphocytes will then fight the infection. After the infection has been cleared, some lymphocytes persist, constituting immunological memory, which ensures a more rapid and effective response upon a subsequent encounter with the same antigen. Lymphocytes develop and mature in the primary lymphoid organs; the bone marrow and the thymus, while activation and accumulation occur in the secondary lymphoid organs; the lymph nodes and the spleen. The peripheral lymphoid organs are specialized for trapping antigen, allowing for initiation of immune responses and providing signals that sustain recirculation of lymphocytes. The whole system is inter-connected by a network of lymph- and blood vessels that transport lymphocytes and antigens until they encounter one another in the secondary lymphoid organs. 1.2 Function of lymphocytes B lymphocytes The specific immune system consists of B lymphocytes and T lymphocytes, which have very different ways of recognizing antigen. The antigen receptor of B lymphocytes, the B cell receptor (BCR), is termed antibody or immunoglobulin (Ig). Each developing lymphocyte generates a unique antigen
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