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PHL 633 Immunotoxicology Seventh Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212 Email: [email protected] Acquired Immune Responses, Cell mediated Macrophages and dendritic cells (including Langerhans cells in the skin) and Kupffer cells in the liver, have an important role in the development of specific immune responses to pathogens in that they process and present antigens to T lymphocytes The T- cell antigen receptor (TCR) recognizes and binds proteolytically processed short peptide fragments (antigens) bound to self major histocompatibility complex (MHC) molecules on the surface of an APC There are two major classes of MHC molecules that present different types of antigens to different types of T cells: I. Class I MHC generally presents peptides derived from proteins produced within the cell (e.g., viral or tumor antigens) and is recognized by CD8 T cells II. Class II MHC generally present peptides derived from proteins taken up by the cell and is recognized by CD4 T cells In addition to the TCR, other molecules contribute to activation of T cells either by functioning as co-receptors that initiate nonspecific, co- stimulatory signal transduction events or by increasing the avidity of the interaction with the antigen-presenting cell Acquired Immune Responses, Cell mediated Acquired Immune Responses, Cell mediated Acquired Immune Responses, Cell mediated Acquired Immune Responses, Cell mediated Binding of antigen presented on MHC to a TCR is the major interaction that must occur between APCs and T cells to initiate an acquired immune response Subsequent to this initial interaction, costimulatory molecules must be engaged on both the T cells and APCs to sustain and direct the immune response One of the best characterized interactions occur between CD28 on the T cells and B7.1 (or CD80) on the APCs, which provide a more robust immune response as measured by clonal expansion and cytokine production, such as IL-2 Other important interactions between cells include CD40–CD40 ligand (on APC–T cell, respectively), which sustains clonal expansion and differentiation of the T cells, and provides activation signals to the APC Other important interactions between cells include CD40–CD40 ligand (on APC–T cell, respectively), which sustains clonal expansion and differentiation of the T cells, and provides activation signals to the APC Acquired Immune Responses, Cell mediated Acquired Immune Responses, Cell mediated Acquired Immune Responses, Cell mediated Acquired Immune Responses, Cell mediated T cells that express CD8 mediate cell killing (CTL); whereas T cells that express CD4 mediate helper functions through coordinated interactions with other cells A recently described population of T cells, the T-regulatory cells, are a subset of CD4+ T cells that express CD25 and the transcription factor Foxp3 These cells act to suppress T-cell function and prevent uncontrolled immune responses Mature T cells are found in the lymph nodes, spleen and peripheral blood Upon MHC plus antigen binding to the TCR, the mature T cell becomes activated and, after proliferation, undergoes differentiation into either an effector cell or a memory T cell Effector T-helper cells can subsequently differentiate into either a Th1 or a Th2 phenotype Th1 cells predominantly express IL-2 and IFN-γ and promote CMI and delayed-type hypersensitivity (DTH) Th2 cells predominantly express IL-4, IL-5, IL-6, IL-10, and IL-13 and promote humoral immune responses. Although the two populations are not mutually exclusive, they do negatively regulate each other, such that a strong Th1 response suppresses a Th2 response and vice versa Acquired Immune Responses, Cell mediated Acquired Immune Responses, Cell mediated Acquired Immune Responses, Cell mediated Acquired Immune Responses, Cell mediated Acquired Immune Responses, Cell mediated Acquired Immune Responses, Cell mediated