The survival and function of T cells in vivo is controlled by a spectrum of different cytokines, especially by those that interact with receptors associated with the common gamma chain (?c) such as IL-2, IL-7 and IL-15. Contact with these cytokines is especially important for controlling the formation of T cells and maintaining T cell homeostasis in adult life. Exposure to??c cytokines is also crucial for mounting strong immune responses to pathogens and for eliminating tumor cells. It has been known for several years that the lifespan of??c cytokines can be extended by association with specific anti-cytokine monoclonal antibodies (mAb). Recently, formation of IL-2/IL-2 mAb complexes was found to markedly enhance the biological activity of IL-2. Thus, massive expansion of T cells and NK cells occurred after short-term injection of IL-2/IL-2 mAb complexes. Similar effects occurred with injection of mAbs bound to IL-4 or IL-7. A striking finding is that, especially for IL-2, the strong enhancing effect of mAb binding on cytokine function is conspicuous in vivo but largely absent in vitro. Precisely why cytokine/mAb complexes have such potent activity in vivo is still largely obscure, although extending cytokine half-life by FcRn and presentation of the complexes by FcR+ cells appear to be important. These issues will be probed in depth, especially by examining the stimulatory function of the cytokine-mAb complexes in mice lacking FcRn, one or more types of FcR, and both types of receptors. The possibility that the cytokine/mAb complexes function in part by extending cytokine half-life will be assessed by various approaches, including the use of techniques designed to reduce or improve half-life. Elucidating the mechanisms by how cyotkine/mAb complexes display strong biological activity could lead to development of better approaches for treatment of cancer and autoimmune diseases. ?? ?? ?? ?? ARRA JIT Submission: Grant # 1 R01 AI075164-01A2;PI: Surh
The purpose of this proposal is to define novel ways to boost the immune responses against infectious agents and tumors. In particular this proposal will investigate the mechanisms involved in enhancing the immune response by administering T cell cytokines in a modified form that greatly increases the activity of the cytokines.
|Martin, Christopher E; van Leeuwen, Ester M M; Im, Se Jin et al. (2013) IL-7/anti-IL-7 mAb complexes augment cytokine potency in mice through association with IgG-Fc and by competition with IL-7R. Blood 121:4484-92|
|Carrette, Florent; Surh, Charles D (2012) IL-7 signaling and CD127 receptor regulation in the control of T cell homeostasis. Semin Immunol 24:209-17|
|Loewendorf, Andrea I; Arens, Ramon; Purton, Jared F et al. (2011) Dissecting the requirements for maintenance of the CMV-specific memory T-cell pool. Viral Immunol 24:351-5|
|Cho, Jae-Ho; Kim, Hee-Ok; Surh, Charles D et al. (2010) T cell receptor-dependent regulation of lipid rafts controls naive CD8+ T cell homeostasis. Immunity 32:214-26|