Projekt: Role of tumor necrosis factor (TNF) and lymphotoxin produced by T cells and by lymphoid tissue inducer cells in the organization of lymphoid tissues critical for mucosal immunity

Title: Role of tumor necrosis factor (TNF) and lymphotoxin produced by T cells and by lymphoid tissue inducer cells in the organization of lymphoid tissues critical for mucosal immunity

Supervisor:
Prof.  Dr. Sergei Nedospasow  (Teilprojekt A13)
AG Entzündungsbiologie
Deutsches Rheumaforschungszentrum (DRFZ) Berlin
Charitéplatz 1, 10117  Berlin

Contact: Prof. Dr. Sergei Nedospasow; Dr. Jaroslaw A. Prassolov; t: 030 2846 0641/677

Background information/project description: Our group is interested in biology of TNF, lymphotoxin a and ß genes (Lta and Ltß, respectively). These cytokines contribute to different aspects of immune system: organization of lymphoid organ structure, control of immune response and modulation of autoimmune disease activity by blocking products of these genes in vivo. TNF is critical for host defence against different pathogens, such as L. monocytogenes and M. tuberculosis, and in organization of microarchitecture of secondary lymphoid organs, such as spleen, lymph nodes (LNs) and Peyer’s Patches (PPs). Lymphotoxin a and ß in the form of heterocomplex (Lta1Ltß2) is crucial for development and organization of spleen, lymph nodes and PPs. Strikingly, mice devoid of LTa or Ltß genes do not develop LNs and PPs, whereas mice with a deletion of TNF gene lack PPs only. A novel cell type, responsible for development of lymph nodes and gut-associated lymphoid tissue, has been discovered recently. This cells population, so-called lymphoid tissue inducers cells (LTICs), has been found to express high levels of TNF, Lta and Ltß. but role of TNF/LT genes in gut-associated lymphoid tissue remains elusive.
We have generated panel of mice with cell-specific deletion of TNF, Lta and Ltß genes in LTICs and in T cells using site-directed recombination technique, where these cytokines can be addressed. These mice have been evaluated, and they do have expected gross phenotype, but in-depth study is now needed.
We are looking for highly motivated, independently thinking medical student who would like to join our team. He/She will be involved in studying of role of TNF, Lta and Ltß expressed by LTICs in organization of secondary lymphoid organs in normal conditions, which will be done in close collaboration with the group C. Loddenkemper (Charite, Berlin). In proposed study, such techniques as immunofluorescence, immunohistochemistry, FACS analysis will be used. Knowledge of basic molecular biology techniques is desired, but not mandatory.

References:

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    2.     Tumanov, A. et al. Distinct role of surface lymphotoxin expressed by B cells in the organization of secondary lymphoid tissues. Immunity. 17, 239-250 (2002).
    3.     Kruglov, A. A. et al. Physiological functions of tumor necrosis factor and the consequences of its pathologic overexpression or blockade: mouse models. Cytokine Growth Factor Rev. 19, 231-244 (2008).
    4.     Rennert, P. D., Browning, J. L., Mebius, R., Mackay, F. & Hochman, P. S. Surface lymphotoxin alpha/beta complex is required for the development of peripheral lymphoid organs. J. Exp. Med. 184, 1999-2006 (1996).     
    5.     Sun, Z. et al. Requirement for RORgamma in thymocyte survival and lymphoid organ development. Science. 288, 2369-2373 (2000).
    6.     Mebius, R. E., Rennert, P. & Weissman, I. L. Developing lymph nodes collect CD4+CD3- LTbeta+ cells that can differentiate to APC, NK cells, and follicular cells but not T or B cells. Immunity. 7, 493-504 (1997).
    7.     Eberl, G. & Littman, D. R. Thymic origin of intestinal alphabeta T cells revealed by fate mapping of RORgammat+ cells. Science 305, 248-251 (2004).