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
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 ittolerance
-Ag presented in presence of dangerproductive immune response
Ex of Danger Signals: Molecules released during injury and necrotic cell death (heat shock
-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
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
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
-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 attainedAutoimmunity (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