Integrin CD11b and its role in immune suppression

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DESCRIPTION (provided by applicant): Orally-induced immune tolerance (oral tolerance) has great potential in clinical applications, such as rheumatoid arthritis, owing to its specific and long-lasting immune suppression. However, the current oral tolerance-based therapy suffers from low therapeutic efficacy, which prevents it from actual use in human patients. Thus, our long term goal is to determine the molecular and cellular processes underlying oral tolerance-mediated immune suppression. Recent studies demonstrate that the development of oral tolerance is dependent on antigen-presenting cells (APC), including CD11b+CD11c- macrophages and CD11c+ dendritic cells (DC), and also on the formation of a distinct CD4+CD25+ T regulatory (Treg) cell population that expresses the transcription factor Foxp3. Two distinct subtypes of Foxp3+ Treg cells have been identified in vivo: the naturally occurring Treg cells (nTreg) and the adaptive/induced Treg cells (iTreg). In this application, we propose to study how integrin CD11b/CD18 (Mac-1, 1M22), a receptor that is highly expressed on macrophages and DC, facilitates the establishment of oral tolerance. Our preliminary results demonstrate that genetic inactivation of CD11b does not affect immune activation, DC differentiation, or the number of total CD4+CD25+Foxp3+ Treg cells under oral tolerance-inducing conditions; but it completely abolishes antigen- induced oral tolerance. We show that deficiency of CD11b/CD18 in mice leads to enhanced expression of IL-6 and preferential immune deviation toward Th17, a distinct T cell lineage characterized by the production of large quantities of IL-17. In addition, we show that adoptive transfer of CD11b+CD11c- macrophages but not CD11c+ DC could restore the defective oral tolerance in CD11b-/- mice. Based on these discoveries, we hypothesize that CD11b facilitates the development of oral tolerance by suppressing Th17 differentiation. We plan to test our hypothesis in two specific aims. First, in light of the recent report showing that nTreg cells are not required for oral tolerance, we will test our hypothesis that CD11b deficiency specifically affects the generation or function of Foxp3+ iTreg cells, using CD11b-/-OTIIRag1-/- mice and Foxp3(gfp)OTIIRag1-/- transgenic mice, which will enable us to better monitor the generation and function of iTreg cells in the peripheral lymphoid organs under oral tolerance inducing conditions. In Specific Aim 2, we will test the hypothesis that CD11b deficiency abrogates oral tolerance by enhancing IL-6 production by mucosal macrophages, using function-blocking antibodies against IL-6 and IL-6 receptor, as well as IL-6-/- mice. Given the potential of oral tolerance in the treatment of various autoimmune diseases, the information generated from this project will not only helps us better understand the biology of immune tolerance, it may also offer us better strategies to enhance the therapeutic efficacy of oral tolerance-based therapies. PUBLIC HEALTH RELEVANCE: Completion of this study will provide novel insights into the unique role of integrin CD11b in the development of oral tolerance by regulating the balance between Treg and Th17 differentiation. Given the strong association between Th17 cells and various autoimmune diseases in human patients, the information generated may also help us design better oral-tolerance-based regimens that can be used in clinical applications for the treatment of autoimmune diseases.