Investigations on antigen-dependent and -independent functions of distinct myeloid subsets of phagocytes in host defence and maintenance of self-tolerance during infection and inflammation

• Applicant: Professor Dr. Stefan Uderhardt
• Subject Area: Immunology ; Rheumatology
• Term: from 2014 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 255918677

The immune system uses a variety of innate and adaptive (antigen-specific) effector modalities to protect the host against pathogen invasion. These immune defenses are potent and can cause substantial damage to host tissues, requiring a layered and interwoven array of control mechanisms to limit such collateral damage during and after infection. A key locus of such control is at the level of antigen presentation to cells of the adaptive immune system during periods of inflammatory tissue damage, when the immune system must meet two competing obligations - to promote an effect anti-pathogen response through immunogenic presentation of microbial antigens and limit anti-self responses by avoiding such immunogenic display of self-antigens. In recent work from the applicant, it was demonstrated that a major mechanism used to achieve this end involves the specialization of subsets of phagocytes (myeloid cells), such that inflammatory macrophages preferentially acquire and present pathogen-derived over self-derived material, while another population of non-immunogenic phagocytes takes up and disposes tissue debris. These cell-type specific activities are also coordinated between the cell subsets via lipid mediators that limit uptake of self-components by the immunogenic inflammatory phagocyte subset. In this proposal I detail plans for extending these initial observations at the cell and molecular levels, (1) defining more thoroughly the subset specific role of distinct myeloid cells in various sites and under different conditions of infection and inflammation that engage in these dichotomous activities of tissue clearance vs. initiation of anti-pathogen effector responses, (2) identifying the receptors and signaling mechanisms that underlie these different functionalities, and (3) defining the integrated function of these cells through cross-regulatory connections. When placed in the larger context of additional mechanisms that enforce immune homeostasis, such as regulatory T cells, feedback expression of inhibitory receptors, central and peripheral deletional mechanisms, and the like, the results of these investigations will help identify components of the regulatory apparatus whose malfunction can give rise to autoimmune disease and suggest targets for future therapeutic efforts.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Ronald N. Germain, Ph.D.