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Purpose/Objective: Memory T cell formation is the result of an intricate balance between extracellular cues and intracellular signaling components. PI3K-signaling is associated extensively with effector cell differentiation, but its inhibition during T cell activation results in apoptosis of all cells, including memory precursors. This suggests a vital role for PI3K-signaling in memory cell formation. NKG2D is an activating receptor which potentiates cytotoxic cell function by stimulating the PI3K pathway. On CD8 T cells its expression is induced after activation, but long before target tissues are encountered. In this study, we investigated whether NKG2D is involved in the formation and maintenance of CD8 memory T cells. Materials and methods: In order to specifically study the function of NKG2D on T cells, mice deficient for NKG2D and Dap10 were used, on a wild type or T cell receptor transgenic background. Full knockout mice were used, as well as mixed bone marrow chimeric mice and adoptive transfer models of transgenic T cells. T cell responses were assessed in vivo using LCMV, mCMV and Listeria monocytogenes infection models. In addition, a novel in vitro memory cell differentiation model dependent on IL-15, was developed to specifically study intracellular signaling. Results: We show that upon viral infection NKG2D does not only enhance cytotoxicity of effector cells, but also mediates memory CD8 T cell formation. In vivo, NKG2D requires Dap10 to promote memory cell formation in a process that involves IL-15. In vitro, we demonstrate that NKG2D potentiates IL-15 mediated PI3K signaling in a narrow timeframe after activation, early during memory cell differentiation. Inhibition of PI3K or NKG2D signaling during this stage resulted in cell death of memory precursor cells and impaired memory formation. Ablation of NKG2D was accompanied by enhanced T-bet expression, effector cell differentiation and reduced survival. Conclusions: Here, we show a novel and crucial role for PI3Kmediated survival signaling early during memory cell differentiation, which is controlled by the IL-15/NKG2D axis. Our findings provide new insights in how these receptors may control both cytotoxicity and memory T cell differentiation. Moreover, it provides an important new therapeutic window for enhancing T cell based immunotherapy.

Cytomegaloviruses (CMV) are members of the herpesvirus family. They share many similarities at the molecular level with herpes simplex virus, the prototype of the herpes group, but also many differences, The molecular differences are reflected in different biological manifestations of infection. This communication presents a brief overview of the replication cycle of human and murine CMV, with emphasis on the structural changes of the host cell induced by infection and events associated with assembly of the virions.

Major histocompatibility complex (MHC) class I-encoded molecules are thought to play a major role in cytomegalovirus biology. Murine cytomegalovirus (MCMV) immune control is principally governed by CD8+ MHC class I-restricted T-lymphocytes that recognize antigens which are presented through the MHC class I antigen-processing pathway. However, depletion of these cells by in vivo administration of cytolytic monoclonal antibodies does not alter the kinetic of MCMV control, indicating that the immune system can expand an alternative compensatory mechanism if the class I-restricted mechanism is absent. During expression of the replicative programme in an infected cell, MCMV interferes with the MHC class I pathway. Early gene products retain correctly folded MHC class I complexes in the Golgi compartment, thereby causing a block in antigen presentation.