Controlling Th2 immunity by tuning CXCL13 dependent DC migration in lymph nodes

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DESCRIPTION (provided by applicant): CD4 T cells, particularly IFNγ-producing Th1 cells, provide protection to intracellular pathogens like Leishmania major. By contrast, IL-4 producing Th2 cells are not protective and mice (and humans) that make a Th2- dominated response to this pathogen are highly susceptible to disease. Unfortunately, there are significant gaps in our understanding of why some individuals cannot make the protective T cell response upon infection. Our data suggests that dendritic cells (DCs) play a key role in this process, but to date, we do not know what signals direct the DCs to initiate Th2 development. Until we can identify these DC programming signals and understand how they change the functional properties of the DC, the long-term goal of developing therapeutics that can "re-direct" non-protective or pathogenic Th2 responses to parasites such as Leishmania or allergens like House Dust Mite will remain elusive. The major objectives of this proposal are to identify the key signals in the infected tissue and lymph node (LN) that are required to make DCs competent to initiate a Th2 response following Leishmania infection and to determine whether we can manipulate those signals to induce immune protection in susceptible strains of mice. The rationale for the proposed research is that a better understanding of how DCs are programmed by the pathogen and the cells within its microenvironment to induce Th2 development will lead to the identification of new molecular and signaling pathways that might be exploited to divert or suppress non-protective or pathogenic Th2 immune responses. The central hypothesis that will be tested is that DCs are conditioned by both the pathogen and the microenvironment to acquire Th2 priming capability and that drugs which interfere with either of these conditioning steps in DC maturation can be used to prevent the development of the non-protective Th2 response to Leishmania. The Specific Aims that will test this hypothesis include: (1) identifying the intrinsic and extrinsic signals that program DCs to express CXCR5 following L. major infection, (2) identifying the cellular and molecular conditioning signals provided within the CXCL13-expressing LN microenvironment which facilitate DC-mediated Th2 development and (3) determining whether we change the course of leishmaniasis by modulating CXCL13 or lymphotoxin levels. The proposed approach is conceptually innovative in that we are moving beyond the current CCR7-centric paradigm to test how different microdomains in the LN program DCs to initiate Th2 priming. In addition, the proposal is innovative in that it will addres whether therapeutics that interfere with the migration of these CXCR5+ DCs within the LN microenvironment can be used to treat Leishmania-susceptible strains of mice. The proposed research is significant because it will significantly advance our understanding of how DCs acquire the ability to prime Th2 cells and because it will identify new pathways that can be targeted to intervene in Th2-mediated diseases, like non-curing progressive Leishmanasis, RSV and asthma.