IMMUNOLOGY T CELL TOLERANCE

IMMUNOLOGY T CELL TOLERANCE -Generation of diversity is a stochastic post germ line encoded event. -The ability to discern btw harmful and innocuous antigens is learned in the neonatal period -Auto reactive lymphocytes recognize self antigens and are deleted. -Foreign antigens introduced during that period would also induce tolerance -“Horror autotoxicus” would result from a break down of tolerance to self (ex: Diabetes I attacks Islet cells) OLD VIEW: Self-nonself / antigen driven / developmentally determined NEW VIEW: context model/ circumstance driven/ determined by milieu Context Model for Self-Non Self Distinction -Immune system activated by PAMPS (ex: LPS on pathogens) triggering PRRs (ex: toll receptor) -Adjuvant induced activation necessary for productive IS. Without ittolerance Danger Theory -Ag presented in presence of dangerproductive immune response Ex of Danger Signals: Molecules released during injury and necrotic cell death (heat shock proteins) -Ag presented in absence of danger tolerance -Decision of Tolerance or Productive Response by State of APC When activated b/c of infection, inflammation, PAPMPS or danger, d APC upregulates: Signal One: Presentation of antigen to T cells. Alone anergy/deletion Note: APC doesn’t need costimulation once it is activated! Signal Two: Costimulatory molecules. Both signals  T cell activation Ex: CD28 on T cell binds B71 or B72 on APC Note: Origin of antigen is irrelevant, what matters is the environment it is recognized in (circumstance driven) Thus, Peripheral tolerance plays a critical role in preventing horror autoxicus. Mechanism of T Cell Tolerance (Thymus: Central Tolerance) -Thymus is where T cells develop and are educated. -Positive Selection = only T cells that can interact with self MHC molecules mature to CD4 + CD8+ -Negative Selection= T cell that binds to tight to peptide-MHC complex is eliminated (prevents self attack) NOT ENOUGH FOR EVERY SELF PEPTIDE IN THE BODY, SO TO INDUCE TOLERANCE. . . . Mechanisms of Peripheral Tolerance 1. Ignorance 2. Clonal Deletion 3. Anergy 4. T-regulatory cells 5.Immunoregulation IGNORANCE -auto reactive T cells found in the periphery but to do not respond and cause autoimmunity because (1)low levels of antigen (2)antigen sequestered -If access to abundant self Ag is attainedAutoimmunity (ex: Multiple Sclerosis) CLONAL DELETION -auto-antigen present at high levels and T cells are eliminated (after initial proliferation) T CELL ANERGY -T cell specific for a genetically engineered self antigen expand and then are rendered anergic. -T cells that only rec