Autoimmunity

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T cells
Jan Novák
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The immune system

• Protection against infectious agents
• Clearance of dying, damaged and dangerous cells
• Regulation of the immune responses

3
The immune system

• Non-specific defence mechanisms
• Innate immune system
• Adaptive immune system

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The adaptive immune system

• T cells - cellular immune responses
• B cells humoral immune responses

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T cells

• Central role in the immune system
• Coordination of the immune response
• Cytotoxic functions
• Suppression of the immune responses

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T cells versus B cells

• Minimal morphological differences
• Differentiation based on the detection of surface
  markers
• B cells CD19, B220,
• T cells TCR, CD3, CD4, CD5, CD8 etc.

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T cell receptor (TCR)

• Antigen recognition (?? CD4/8 MHC class I/II)
• Signalization (CD3 transmembrane complex)
  defosforilations
• Proliferation, differentiation, effector functions

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Phenotype of T cells

• T cell receptor (TCR)
• Other receptors involved in the antigen
  recognition and signalization (CD4, CD8, CD3)
• Receptors and molecules involved in the migration
  of T cells
• Receptors for cytokines
• Activation markers (CD25, CD28, CD69)

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T cells

• ?? - T cells
• CD4 helpers
• Th1
• Th2
• Th3
• Th17
• CD4CD25
• CD8 cytotoxic T cells
• iNKT (CD4CD8- a CD4-CD8-)
• ?? T cells

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The pathway of T cell development
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Thymus
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Today
Thursday
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TCR development

• The development of infinite repertoire of TCRs
• Each TCR of each T cell can recognize one antigen
• The repertoire of all TCR has the capacity to
  recognize any antigen

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Formation of TCR repertoire

• Organization of genes coding for TCR is similar
  to the genes coding for immunoglobulins
• Gene complexes TCR? (TCR?) ??? gene complex for
  IgH
• Gene complexes TCR? (TCR?) ??? gene complex for
  IgL

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TCR development

• TCR is encoded by several gene segments
• V - variability
• D - diversity
• J - joining
• C - constant

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TCR development

• Random rearrangement of V,D,J and C segments
• Recombination of gene segments (D-J, V-D)
• Recombination controlled by RAG

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TCR development

• Rearrangement of gene segments for ? chains
• Expression of pre-TCR
• ? chain
• CD3 complex
• pre-? chain
• Rearrangement of gene segments for ? chains
• Formation of definitive TCR

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Central education/deletion
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The maintenance of T cell tolerance
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T cells

• ?? - T cells
• CD4 helpers
• Th1
• Th2
• Th3
• Th17
• CD4CD25
• CD8 cytotoxic T cells
• iNKT (CD4CD8- a CD4-CD8-)
• ?? T cells

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CD4 T cell activation
MHC class II TCR-CD4 interaction
CD4 T cell
APC
Costimulation CD80/86-CD28
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CD4 T cells T helpers
Th1
IL-12
IL-4
Th2
Th0
Th0
APC
TGF-?
TCR MHC interaction
Naive Th0 cell
Th3
Cytokine milie
Engagement of costimulation pathways
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Th1 cells

• Inflammatory cells
• Production of cytokines
• interferon (IFN) ?
• interleukin (IL) 2
• tumor necrosis factor (TNF) - ?

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Th1 cells

• Help to macrophages (M?)
• Activation of M? (IFN??
• Stimulation of their killing activities
• Elimination of intracellular agents

• Help to T cells
• Differentiate into Th1 profile (due to the IL-12
  production by APC)
• Secretion of autocrinne growth factor of T cells
  IL-2

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Th1 cells

• Involved in the clearance of intracellular
  pathogens
• Involved in the delayed type of hypersensitivity
• Involved in some autoimmune diseases

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Th2 cells

• Production of cytokines
• IL-4
• IL-5
• IL-6
• IL-13

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Th2 cells

• Help to B cells
• Antibody production by B cells is dependent on
  the help of T cells (Th2)
• Cytokine dependent help IL-4
• Cell contact dependent help CD40 (B cell) -
  CD154 (T cell) interaction

Th3
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Th2 cells
Specific (direct) help
Nonspecific (bystander) help
T
T
APC
APC


Th3
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Th2 cells

• Participation in the defense against
  extracellular agents
• Participation in the allergic reactions

Th3
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Th1 Th2 competition

• Th1 cytokines inhibit the development of Th2
  responses
• Th2 cytokines inhibit the development of Th1
  responses

Th3
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Th3 cells

• Develop in the presence of TGF-?, IL-10 and IL-4
• Secretion of TGF-? and IL-10
• Induced after oral administration of antigens,
  play a role in the induction of oral tolerance

Th3
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Cytotoxic CD8 T cells

• Elimination of dangerous cells
• Direct elimination of cells infected by
  intracellular pathogens
• Elimination of stressed cells (tumors, damaged
  cells)

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Activation of CD8 T cells
Recognition, activation
CD4 help
CD8
MHC class I - TCR
CD8
APC
Somatic cell
APC activation

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Killing by CD8 T cells

• Perforin-granzyme system (degranulation,
  perforation, apoptotic death)
• Fas-FasL interaction (apoptotic death)
• Cytokine dependent -lymphotoxin (apoptotic death)

CD8
Somatic cell
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Killing by CD8 T cells Perforin-granzyme
system
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Killing by CD8 T cells Fas dependent
killing
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CD8 T cells in immune reactions

• Clearance of infected cells viruses, bacteria,
  parasites)
• Elimination of tumor cells in cooperation with NK
  cells
• Elimination of dying and damaged cells

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Literature

• Immunobiology The immune system in health and
  disease Charles A. Janeway Jr., Garland
  Publishing, 2001
• The autoimmune diseases Noel A. Rose, Academic
  Press Third edition, 1998
• Medical Immunology Tristam G. Parslow, Lange
  Tenth edition, 2001
• Nature Reviews Immunology

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