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• W2483753885 endingPage "292" @default.
• W2483753885 startingPage "255" @default.
• W2483753885 abstract "Activation of T lymphocytes is a critical component of the immunological response to foreign protein molecules. T-cell receptor recognition of peptide-loaded major histocompatibility complex molecules provides antigen specificity and initiates the required steps for T-cell activation, although additional signals are needed for complete T-cell activation. CD28 signaling causes the initial activation of naive CD4 T cells by increasing the sensitivity of the T cell to antigen receptor engagement, and as a result proliferation is induced at otherwise submitogenic concentrations of antigen. A major consequence of CD28 signaling is protection from cell death. The two dominant pathways of apoptosis in T cells are receptor mediated (i.e., tumor necrosis factor family) or mitochondrial-associated proteins (i.e., the Bcl family), both of which are modulated via CD28 signaling. So, an understanding of costimulation and the mechanism by which it regulates immune responses provides new avenues for the development of therapeutics. As CD28 decreases the threshold required to activate naive T cells, as well as increasing the survival of activated T cells, one can envision development of drugs that either potentiate or downregulate an immune response. Further CD28 requirement of memory CD8+ T cells for expansion has been shown in multiple viral infections such as influenza type A virus, HSV, vaccinia virus, and murine gamma herpes virus and is required for rapid pathogen clearance. Costimulatory molecules have been shown to not only help in the generation and maintenance of virus-specific memory CD8+ T cells, but are also important for the reactivation of memory CD8+ T cells and secondary responses. This information has important implications in designing efficient vaccination strategies against pathogens and tumors which can down-regulate costimulatory signals. Moreover the transfusion of T cells, also called adoptive T-cell therapy, is an effective treatment for viral infections and has induced regression of cancer in early stage clinical trials. Adoptive T-cell therapy for cancer is a form of transfusion therapy consisting of the infusion of various mature T-cell subsets with the goal of eliminating a tumor and preventing its recurrence. Second-generation chimeric antigen receptors (CARs) have been generated in which intracytoplasmic domains, derived from costimulatory molecules such as CD2837, or CD134/OX40, or CD137/4-1BB, are incorporated within CARs to fully activate T cells. Second-generation CARs were constructed to provide signaling both through the CD3 zeta chain and, primarily, the CD28 costimulatory molecule by placing the signaling domains in series as a single gene multidomain product. Constructs with the CD28 signaling domain proximal and the zeta chain distal to the membrane were found to be better expressed than constructs with the opposite orientation, and were capable of mediating up to 20 times more interleukin (IL)-2 production upon stimulation with solid-phase antigen compared with first-generation CARs. Subsequently, CAR constructs with costimulatory signaling domains from CD28, inducible costimulator (ICOS), OX40 (CD134), or 4-1BB (CD137) in series with the CD3 zeta signaling region were evaluated using resting human primary T cells. It was found that second-generation CARs, when providing any of these B7 or tumor necrosis factor receptor family costimulatory signals in series with CD3 zeta, confer self-sufficient antigen-driven clonal expansion and enhanced effector function in resting human T cells. Furthermore, addition of the CD28 signaling domain to CARs has been shown to enhance CAR T-cell resistance to regulatory T cells." @default.
• W2483753885 created "2016-08-23" @default.
• W2483753885 creator A5079529210 @default.
• W2483753885 date "2015-01-01" @default.
• W2483753885 modified "2023-09-24" @default.
• W2483753885 title "T-Cell Costimulation and Its Applications in Diseases" @default.
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