The cytokine receptor chain gamma/c is a common signaling component of IL-2 receptor (R), IL-4R, IL-7R, and IL-15 R complexes. Importantly, these cytokine R complexes are expressed on T cells and they all deliver activation signals. We propose to develop small peptide fragments that bind selectively to the gamma/c chain and that deliver cytokine- dependent signals through the gamma/c chain. Such reagents, to be termed as """"""""multikines"""""""", would promote cytokine-independent activation of T cells and, thus, may prove to be useful to initiate protective immunity against cancers and infectious pathogens. Conversely, we will also develop """"""""multikine antagonists"""""""", i.e., peptides that interfere with cytokine-mediated signaling through the gamma/c chain; this reagent would suppress T cell activation and, thus, may prove to be useful in the treatment of T cell-mediated inflammatory diseases.
Our specific aims are: 1) To identify peptides that bind selectively to the gamma/c chain using a phage display strategy. Gamma/c chain-binding peptides will be isolated by panning of a M13 phage library (consisting of random 12-mer peptides fused to a minor coat protein) over COS cells transfected with a full-length cDNA encoding mouse gamma/c chain. 2) To select the gamma/c-binding peptides that deliver or block cytokine- mediated activation signals. We will select the peptides (multikines) that trigger cytokine-independent proliferation of a murine T cell line 7-17 DETC and the peptides (multikine antagonists) that block 7-17 DETC proliferation induced by IL-2, IL-7, or IL-15. 3) To study the in vivo function of multikines and multikine antagonists in mice. We will employ two mouse models of T cell-mediated immune responses (i.e., contact hypersensitivity and skin tumor rejection) to test the in vivo potential of the multikines (and multikine antagonists) to augment (and suppress) immune reactions. We anticipate that these studies may directly lead to the development of an entirely new class of immuno- regulatory agents that control directly the fate of effector (and pathogenic) T cells.
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