T Cell Development and Activation PDF

T Cell Development and Maturation 5  Thymus Immature thymocytes move from the bone marrow to the cortex of the thymus, and exist in the presence of branched cortical epithelial cells and macrophages. The...

T Cell Development and Maturation 5  Thymus Immature thymocytes move from the bone marrow to the cortex of the thymus, and exist in the presence of branched cortical epithelial cells and macrophages. The medulla consists of mature thymocytes, medullary epithelial cells, dendritic cells, and macrophages. Hassall’s corpuscles are present in the thymus, and are believed to be sites of cellular destruction and/or commitment of cells to the regulatory T cell (Treg) lineage. Macrophages in the thymus remove T cells that fail to mature properly. 6  Involution of the Thymus At birth, the T-cell-producing tissue of the thymus begins to be gradually replaced with fatty tissue through a process known as involution of the thymus. The micrographs compare a section of a thymus from a 3-day-old (a) with one from a 70-year-old (b). Mature peripheral T cells are either long-lived, self-renewing, or both. Alternatively, B cells are generated from the bone marrow throughout life. 7  T Cell Development Within the Bone Marrow T cells leave the bone marrow committed to the T cell lineage, but with their germline genes unrearranged. These cells express neither CD4 nor CD8 (double negative), and cannot recognize antigens 8 They home to the thymus where maturation begins.  Gene Rearrangements Within T Cells Similar to B cell gene rearrangements (VDJ and VJ). Occurs in the thymus 9 Diversity for T cells is likely greater because T cells aren’t replenished throughout life. Comparison of Ab and TCR The Fab fragment of an antibody is similar to the TCR – 2 chains with Variable and Constant regions – Antigen recognition occurs at the tip of the variable region The major differences are: 1) antibody monomers can bind 2 antigens simultaneously. 2) antibodies recognize antigen in their native conformation. 3) antibody recognition does not require processing and presentation of antigen. 4) MHC restriction is not required for antibodies. 5) antibodies actually function as effector molecules while the TCR is a receptor that activates an effector cell. -Antibodies are secreted and can act from a distance, while T cells exert their effect (cytokine production or cytotoxicity) in a local area. 10  T Cell Arrives at the Thymus Notch-1 Signaling Initiates Maturation Notch-1 on thymocytes interacts with Notch ligand on thymic epithelial cells, removing transcription repressors from the DNA in the thymocyte Transcription co-activators are attracted, stimulating transcription and maturation of the T cells within the thymus. 11  T Cells in the Thymus Gene Rearrangements For the majority of our discussions, we will be referring to αβ T cells, and not γδ T cells. 12  T Cells in the Thymus The Pre-T-Cell Receptor Similar to what occurs during B cell development with surrogate light chain expression, the β chain is tested at the cell surface using a surrogate α chain known as pTα. This pre-T-cell receptor is expressed in the context of the signaling molecules that are required for T cell activation (CD3 complex). Once an appropriate β chain has been identified, it is removed from the cell surface, and rearrangement of the α chain is induced. 13 Gene Expression During T Cell Development Compare and contrast with genes expressed during B cell development. Be aware of genes specific to T cells, like Zap-70, CD3, CD4, and CD8. 14