This grant proposes to determine the role of Interleukin 16 in accumulation and function of T regulatory cells. While IL-16 was originally described as a chemotactic factor for CD4+ T cells, in models of antigen-induced airway inflammation, it is a potent inhibitor of the Th2 response. Inhibition of Th2 inflammation can, in part, be explained by IL-16 binding to CD4 which uncouples CD4 from the TcR complex inhibiting antigen and allogeneic T cell activation and by selective chemoattraction of Th1 cells. However, in addition, our preliminary data demonstrate that IL-16 is selectively chemotactic for CD4+CD25+CTLA4+ T cells which fail to proliferate to anti-CD3 and which inhibit autologous T cells proliferation to anti-CD3 defining them as T regulatory cells. Unlike TGF-beta, IL-16 is sufficient to induce FoxP3 expression without a second signal. In addition, following 2 weeks of culture with IL-16+IL-2, NWNAT cells develop a CD4+ CD25+ neuropilin-1 + phenotype which correspond with T regulatory suppressor function. Last, we show that thymus and lung T cells from IL-16-/- mice are deficient in expression of CD25 on CD4 cells (CD4+CD25lo) and have fewer CD4+ CD25+ neuropilin-1+ T cells. Intratracheal administration of IL-16 corrects these abnormalities in CD4+CD25+ T cells in the lung in IL-16-/- mice, while thymus and splenic continue to contain CD4+CD25lo T cells and as predicted, IL-16-/- mice exhibit enhanced Th2 inflammation in the lung when challenged with OVA. Our overall hypothesis is that, in addition to its direct effects on TcR signaling, IL-16 also modulates Th2 type airway inflammation by chemoattraction and expansion of T regulatory cells.
Three aims will address this hypotheses by: 1. Determining the phenotype of T regulatory cells that migrate to IL-16 in comparison to T regulatory cells that migrate to TGF-beta;2. Determining the phenotype and function of T regulatory cells expanded in vitro in response to IL-16;and 3. Demonstrating the function of IL-16 responsive T regulatory cells by introducing them in vivo in a mouse model of antigen-induced inflammation.
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