SVIBOR - Project code: 1-08-308

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Project code: 1-08-308


ROLE OF CELL SURFACE MOLECULES IN T CELL DIFFERENTIATION AND FUNCTION


Main researcher: MARUŠIĆ-GALEŠIĆ, SUZANA (122180)


Assistants
Type of research: basic
Duration from: 01/01/92. to 12/31/94.
Papers on project (total): 9
Papers on project quoted in Current Contents: 5
Institution name: Institut "Ruđer Bošković", Zagreb (98)
Department/Institute: Division of Molecular Medicine Department of Biology and Medicine Ruđer Bošković Institute
Address: Bijenička 54
City: 10000 - Zagreb, Croatia
Communication
Phone: 385 (01) 4561 113
Phone: 385 (01) 4561 114
Fax: 385 (01) 424-239
Summary: We have investigated function and differentiation of T cells developing in the enviroment lacking normal expression of MHC class I molecules. In mice with targeted disruption of beta-2 microglobulin, the expression of MHC class I is highly deminished as well as the development of CD8+, cytotoxic T cells. However, these mice cope well with most infectious agents tested. We attempted to investigate whether CD4+ T cells have taken over some of the cytotoxic function, compensating the lack of the major cytotoxic T cell subset in these mice. We found that the number of cytotoxic T cells among CD4+ subset is higher than in mice having normal number of CD8+ T cells. We have also investigated the activation requirements for the two major T cell subsets, CD4+ and CD8+. We found that the proliferation of CD8+ T cells is more sensitive to the presence of immunosuppressive drug, cyclosporin than CD4+ subset. This sensitivity is not due solely to the lower capacity of CD8+ subset to produce lymphokines. Namely, the suppression of proliferation in the presence of cyclosporin A is also observed for the CD8+, CTLL clone, which proliferation depends solely on the externally provided interleukin 2. FINAL SUMMARY Many diseases are caused by ill-regulated immune response. It is therefore essential to learn more about the rules that govern T cell differentiation and function. One of the most critical molecular interactions that regulate both T cell development and function is between antigen receptor on T cells (TCR) and MHC molecules on thymic and extrathymic stromal cells. In our experiments, we used mice in twhich TCR/MHC interaction was disrupted by genetic manipulation or antibody injection. We could than study the consequences of the lack of this interaction on T cells function and development. We have found that the lack of TCR/MHC class I interaction, which results in the absence of CD4-8+ cytotoxic T cells, also leads to expansion of CD4+8- cytotoxic T cells. The expansion of this subset most likelz compensate for the lack of the main cytotoxic subset in these mice. Development of T cells in the absence of MHC class II molecules results in the significant increase in the number of normally rarte CD4-8+, MHC class II-restricted T cells. The simplest explantation of this finding is that the lack of negative selection of T cells with high affinity for MHC class II molecules allows these cells to be positively selected on other MHC molecules. Finally, we have shovn that neonatal blockade of only one MHC class I molecule significanly alters allogeneic response of young treated mice. The results of our experiments contribute to the knowledge about the level of plasicity of T cell function and TCR repertoire.

Keywords: cytotoxic T cells, major histocompatibility complex, MHC molecules, Cyclosporin A, T cell activation, development, function

Research goals: 1. In different experimental models with disrupted MHC/CD4/CD8/TCR interactions we aim to elucidate the requrements for T cell differentiation and function. Also, we will analyse the presence of compenzatory mechanisms operating when one partof immune system is blocked in its function. 2. We will investigade the activation requirements for CD4+ and CD8+, as well as CD4-8-, gamma-delta T cells. We expect to define compenzatory mechanisms enabling immune system to function when some subset is blocked in its function. Also, our experiments will allow us to define some of the diffences in the activation requirements between different T cell subsets, which might be responsible for different functions of these subsets. Unadequatly regulated immune response is a couse of many diseases such as autoimmune, chronic infections and a vide variety of immunodefficiences. Inadequate immune response could be a result of pathological immune response toward self or foreigh antigen or could be caused by altered T cell development. It is therefore essential to learn more about mechanisms of T cell development and function, in order to be able to soundly manipulate this response during disease. The aim of our project was to learn more about the mechanism of differentiation of different T cell subsets which are the main regulators of the immune response. We investigated the role of different molecular interactions during T cell development. The most important, single interaction that governs T cell development and shapes the repertoire of mature T cells is interaction between receptor for antigen on T cells (TCR) and major histocompatibility complex (MHC) molecules on thymic or extrathymic stromal cells. Therefore, we investigated the role of this interaction in the shaping of the TCR repertoire and aquiring T cell function.

COOPERATION - PROJECTS


  1. Name of project: The role of cell surface molecules in T cell adhesion and activation
    Name of institution: Labor Dr Peter Walden, Max-Planck Institute fur Biologie, Abt. Immunegenetik,
    City: 72076 - Tubingen, Germany

  2. Name of project: Adhesion molecules in T cell function
    Name of institution: Max-Planck Institute fur Biologie, Abt. Immungenetik
    City: 72076 - Tubingen, Germany

COOPERATION - INSTITUTIONS


  1. Name of institution: Max-Planck Institute fur Biologie, Abteilung Immunogenetik
    Type of institution: State institute
    Type of cooperation: Other
    City: 72076 - Tubingen, Germany
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