Analyses of signaling mechanisms drive fundamental insights into biological regulation as well as important targets for possible therapeutic interventions. Adaptive immunity and autoimmune disease are determined by signal transduction pathways that regulate the balance among differentiation and fate choices for CD4 and CD8 T cells, and the capacities of different subsets to generate immunological memory. Signals initiated through PI 3-kinases (PI3K) are relayed in part by the pro-survival kinase Akt, whose activation and downstream targets such as the mammalian Target of Rapamycin (mTOR) regulate survival and proliferation. Functions of rapamycin, an immune suppressive drug useful in transplantation medicine, had been equated with mTOR inhibition, but recent findings show that mTOR functions through at least two mutually exclusive classes of multiprotein complexes. The first, mTORC1, is rapamycin-sensitive and regulates aspects of protein translation and cellular growth. However, a second class of mTOR complex, termed mTORC2, is relatively rapamycin-resistant, with inhibition depending on the effective concentration of the drug. While the signaling and biology of mTORC1 have been investigated extensively, little is known about the roles of mTORC2 in normal cell physiology, and nothing in cells of the immune system. Evidence as to the function of mTORC2 in immunity (if any), the mechanism(s) for any such function or its relation to Akt vs. PKC pathways, and whether or not the lack of mTORC2 would mitigate abnormalities stemming from loss of PTEN in lymphocytes are all unknown. Exciting indications suggest complex roles of rapamycin in regulating a balance between effector and memory states for CTL, but nothing is known about the helper lineages in this regard, nor is there insight into how mTORC2 relates to the effect of rapamycin on CTL memory. Thus, the need to understand functions of the mTORC2 complex as part of new frontiers for mTOR signaling in immunity and memory is especially great. Based on our preliminary findings, the central hypotheses of this proposal are (i) that the mTORC2 signaling complex mediates the acquisition of full and appropriately balanced functional capabilities by mature T cells, and (ii) that it regulates their properties and capacity to participate in immunity and autoimmunity using different downstream signal relays depending on the biological target process. To test the central hypothesis and elucidate related mechanisms, we propose to define the roles of mTORC2 in T cell- mediated primary and recall immunity (Aim 1), elucidate mechanisms by which mTORC2 effects T helper differentiation via the HM modifications of Akt- and PKC-8 (Aim 2), and dissect the interplay between mTORC2 and PTEN in regulating T cells (Aim 3). The expected outcome of the proposed studies is that we will (i) change concepts and elucidate how mTOR signaling affects immunity and CD4 T cell fates, &(ii) identify new mechanisms by which signaling through Akt and PKC influence the balance of gene expression programs acquired by this class of T cells, thereby offering the potential for more selective therapeutic targeting.
The precise properties of a class of white blood cells called lymphocytes are central to the effectiveness of immune responses and vaccines but also cause autoimmune diseases and the rejection of organ transplants. Lymphocytes acquire their specific properties as a result of passing signals inside the cell, a feature exploited by effective but problematic immune suppressant drugs such as rapamycin. This research proposal seeks to understand key aspects of how proteins whose function is blocked by rapamycin function in immunity by regulating lymphocytes, and enhance understanding of the way in which vaccines work through 'immune memory'.
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