Immune Responses To Ocular Antigens

National Eye Institute

Investigators

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Abstract

Targeted at learning about inflammatory eye diseases, this project focused in FY 2007 on the involvement in ocular inflammation of a recently discovered subset of T-helper cells, designated Th17. Cells of this subset are identified by their selective expression of interleukin-17 (IL-17), a feature that differentiates them from interferon (IFN)-gamma producing Th1, or IL-4 producing Th2 cells. The specific issues addressed included: (i) a comparison between polarized Th17 and Th1 cells with regard to their capacity to induce ocular inflammation and several other key activities and (ii) involvement of Th1 and Th17 cells in the autoimmune processes triggered by different Toll-like receptors (TLR) ligands.[unreadable] [unreadable] (i) To test the capacity of Th17 to induce ocular inflammation, we used an experimental system developed in our lab in which transgenic T-cells specific against hen egg lysozyme (HEL) are adoptively transferred into mice that express HEL in their lens. When activated, the transferred T-cells induce ocular inflammation (Kim et al., Invest. Ophthalmol. Vis. Sci., 2002, 43:758). When activated in culture in the presence of certain mixtures of cytokines and antibodies, naive cells acquire the phenotype of Th1 or Th17, thus allowing us to obtain lineages of Th1 or Th17 cells and compare them for a host of capacities. Th17 cells were found to resemble Th1 in their capacity to induce ocular inflammation; both lineages induced inflammation at numbers as low as 200,000 cells per recipient. The two lineages differed, however, in their profile of surface markers, in particular markers related to trafficking and maturation. Th1 and Th17 also differed in their capacity to induce massive proliferation of the host lymphoid cells and splenomegaly, with Th1 being superior to Th17 in these activities. These observations shed new light on the newly discovered Th17 cells and their biological activities.[unreadable] [unreadable] (ii) In studies carried out in FY 2005 and 2006 we analyzed the capacity of various microbial products to trigger pathogenic autoimmunity, by their interaction with TLR on antigen-presenting cells. Using the experimental system described in (i) we found that all tested TLR ligands triggered autoimmunity, determined by their capacity to stimulate naive cells and convert them into effector cells, capable of inducing inflammation in recipient mouse eyes in which the target antigen is expressed (the data are detailed in Fujimoto et al., J. Immunol., 177:6896, 2006). Using this experimental system we analyzed in FY 2007 the differential involvement of Th1 or Th17 in the pathogenic processes triggered by different TLR ligands. We found remarkable difference among the tested TLR ligands, as demonstrated by the ratio between Th17 and Th1 in the inflamed eyes. Thus, the ratio between Th17 and Th1 was approximately 4:1, 2:1, 1:1, or 1:2 in mice treated with pertussis toxin, lipopolysaccaride, poly (I:C), or CpG oligodeoxynucleotide, respectively. These findings show for the first time that different microbial products, TLR ligands, are selective in the populations of lymphocytes they stimulate.