All of the functions of Interleukin 16 (IL-16) depend upon binding to CD4. As a result of that relationship, we have hypothesized that CD4 can be viewed as a sentinel molecule, which when bound by MHC/peptide helps transmit a full TcR mediated activation signal. However, when bound by IL-16, CD4 transmits signals sufficient to induce chemotaxis and expression of IL-2R and while transiently preventing TcR signaling. IL-16/CD4 induced expression of IL-R and renders the cells competent to proliferate in response to IL-2 and IL-15. Thus, the IL- 16activated CD4+ T cell is primed to respond inan antigen independent fashion; and is prevented from responding to antigen.
The aims of this grant are to define further MHC II-independent functions for CD4 by exploiting the specific binding and activation relationships between IL-16 and CD4. In particular we will determine the structural requirements onIL-16 and CD4 for binding and activation and explore the signals and functions that result from IL-16/CD4 binding. Based upon our preliminary data, our hypothesis is that directed mutations of IL-16 will result in selective ability to induce the CD4 signals for chemotaxis, IL-2R expression or inhibition of the MLR and TcR by altering IL-16 oligomerization, CD4 binding or CD4 activation. Ultimately, we believe this knowledge will result in development of IL-16/CD4 based strategies for selective regulation of CD4+ T cell function and generate new information about CD4 function.
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