• The activation of T-cells must be tightly controlled to allow for
    • selective proliferation of pathogen specific T-cells
    • anergy of self-reactive T-cells
    • prevention of autoimmune disorders
  • Four events are required for proper T-cell activation including
    • antigen processing and presentation by antigen presenting cells that
      • display antigens as peptides bound to MHC
      • migrate to draining lymph nodes
    • specific binding of the T-cell receptor to the antigen concurrently with
      • binding of CD4 coreceptors to MHC class II in helper T-cells
      • binding of CD8 coreceptors to MHC class I in killer T-cells
    • costimulation of the T-cell by antigen presenting cells through interaction between
      • B7 (CD80/CD86) on dendritic cells
      • CD28 on T-cells
    • differentiation through cytokine signaling pathways at the time of activation
  • After T-cell activation, activated cells migrate to the periphery where
    • killer T-cells identify infected cells and release toxic substances
    • helper T-cells undergo further differentiation into subtypes
Three Signal Hypothesis
  • Antigen presenting cells interact with naive T-cells in secondary lymphoid organs where
    • they allow T-cells to recognize their ingested antigens
    • they provide costimulatory input
  • T-cells require all signals to be present in order to activate
  • T-cells will undergo apoptosis or become anergic (state of inactivity) if
    • they receive only one of the activation signals so that
      • autoreactive cells can be removed
      • benign materials are not mistakenly recognized as harmful
    • they receive signals that the infection is cured and inflammation has subsided
Three Signal Hypothesis
Feature Signal 1 Signal 2
Signal 3
  • Leverage specificity of T-cell receptors to detect antigen
  • Ensure binding to antigen presenting cell with antigen of interest
  • Distinguish between erroneous binding of T-cell receptors and real pathogenic recognition
  • Ensure that the recognized antigen is on an activated antigen presenting cell
  • Convey information about the surrounding environment of the activation site
  • Ensure proper differentiation of the activated T-cells
Interacting proteins
  • Antigen bound to MHC type I or II proteins 
  • T-cell receptor
  • CD4 or CD8
  • B7 (CD80 and CD86) that are only expressed on activated antigen presenting cells
  • CD28
  • IL-2 (T-cell survival signal)
  • Diverse cytokines
  • Cytokine receptors
  • Super antigens can artificially induce binding of T-cell receptor with MHC
  • Induced anergy or apoptosis if not present in conjuction with signal 1
  • Killer T-cells require cytokine help from helper T-cells to activate
Helper T-Cell Differentiation
  • After activation, helper T-cells further differentiate in response to
    • cytokine signals released by the innate immune system
    • the inflammatory environment of the activation site
    • cross talk with other adaptive cells such as regulatory T-cells
  • Each helper T-cell subtype differs in several ways including
    • general function of the class
    • signals (usually cytokines) required for differentiation
    • secreted factors produced
Helper T Cell Subtypes
Feature Th1 Th2
  • Promote cell based immunity
  • Activate macrophages and cytotoxic T-cells
  • Promotes humoral immunity
  • Recruits eosinophils as part of parasite defence
  • Activate neutrophils
  • IFN-γ
  • IL-12
  • IL-2
  • IL-4
  • IL-6
  • TGF-β
  • Granuloma formation
  • Tuberculous leprosy
  • Lepromatous leprosy
  • IgE production by B cells
  • Chronic inflammatory conditions
Secreted Factors
  • IFN-γ
  • IL-2
  • IL-4
  • IL-5
  • IL-13
  • IL-17
  • IL-21






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