Introduction to Autoimmunity

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Introduction to Autoimmunity
Alon Monsonego, Ph.D. The department of
Microbiology and Immunology Tel [phone]
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Topics

• T-cell selection
• T-cell activation
• T-cell regulation

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• The Development and
• Survival of Lymphocytes

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Figure 7-2 part 1 of 2
The development of T cells
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Figure 7-2 part 2 of 2
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Figure 7-8 part 1 of 2
The cellular organization of the human Thymus
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Figure 7-9
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Figure 7-10
The thymus is critical for T-cell maturation
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Figure 7-12
Changes in cell surface molecules throughout
T-cell maturation in the Thymus
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Figure 7-14
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Figure 7-32 part 1 of 2
Positive selection in the thymus
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Figure 7-32 part 2 of 2
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Figure 7-35
Negative selection in the thymus by bone marrow
derived cells
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Figure 7-36
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Figure 13-9
Expression of AIRE in the thymus shape the immune
repertoire
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Summary

• Lymphocytes originate in the bone marrow.
• B cells mature in the bone marrow
• T cells mature in the thymus
• Positive and negative selection mechanisms shape
  the lymphocyte repertoire

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• T Cell-Mediated Immunity

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Figure 8-3
dictate
Distribution of APCs in the lymph nodes
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Figure 8-4
Naïve T cells encounter antigen in the peripheral
lymph node
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Figure 8-13
Two signals are required to induce T-cell
activation
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Figure 8-14
DCs maturation as APCs
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Figure 8-15
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Figure 8-21
T-cell tolerance to antigens expressed on tissue
cells
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Figure 8-24
Activation of CD4 T cells
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Figure 8-31
Effector T cells with different functions
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Figure 8-32 part 1 of 3
T-cell cytokines
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Figure 8-32 part 2 of 3
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Figure 8-32 part 3 of 3
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Molecular differentiation of Th1,Th2, and Th17 T
cells
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Summary

• Antigens are processed and presented to T cells
  by professional APCs (B cells, Mac, and DCs).
• Two signals are required to induce T-cell
  activation by APCs.
• The inflammatory environment shapes the
  activation of both T cells and APCs
• The function of T cells (CD4/CD8) differs
  primarily according to their cytokine profile.

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• Mechanisms of autoimmune diseases

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Figure 13-1
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Figure 13-6
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Figure 13-31
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Figure 13-3
T-cell mediated paralysis in a mouse model of
multiple sclerosis
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Figure 13-34
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Mechanisms of immune regulation

• Regulatory T cells

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Antigen receptors and the immunological synapse
The principal T cell membrane proteins involved
in antigen recognition and in responses to
antigens are shown. The functions of these
proteins fall into three groups antigen
recognition, signal transduction, and adhesion.
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Figure 13-14
By stander suppression
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CD4CD25 cells

• About 5-10 of CD4 cells.
• Generated in the thymus possibly via high
  affinity interactions with self ligands presented
  by thymic stromal cells.
• Extensive proliferation in vivo depending on the
  presence of specific Ag.
• Their development and maintenance is highly
  dependent on costimulation and IL-2.
• Express CD25, TNFa receptor, CTLA-4, and Foxp3.
• MicroRNAs are involved in their differentiation.

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Mechanism of action

• Antigen specificity is unknown but most likely
  selected and respond to self Ags.
• Suppression is contact and also cytokine
  dependent (TGF-b/ IL-10).
• Act in tissues to control inflammation via direct
  effects on effector T cells or DCs.

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Foxp3

• Highly enriched in CD4CD25 cells.
• Its expression induces Treg activity.
• Targeted disruption prevents Treg development and
  results in autoimmune diseases in mice and humans
  (IPEX-immune dysregulation, polyendocrinopathy,
  enteropathy, X-linked). Leads to type-1 diabetes,
  allergy, and other.
• Induced by TGF-b in CD4CD25- cells and lead to
  expansion of CD4CD25 in vitro and in vivo.
• Foxp3 binds other transcrition factors such as
  NFAT, AML1, RUNx1.

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Different subsets of Tregs
CD4CD25 10 of CD4
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A balance between regulation and activation
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Figure 13-15 part 1 of 2
CD4CD25 regulatory T cells inhibit colitis
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Figure 13-15 part 2 of 2
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Anti-ergotypic T cells
CTLA-4-CD80/86
Treg
Teff
TCR-Ag
APC
TCR-Ag
MHC-Ag
TCR
Terg
TCR-Ag(HSP/CD25)
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Tr1 cells

• Produce IL-10 already at 4 hr after activation.
• Express high levels of CTLA-4.
• CTLA-4 dependent production of TGF-b.
• Express both Th1 and Th2 chemokine receptors.
• Proliferate poorly following activation due to
  autocrine effect of IL-10.
• IL-15 induces their proliferation as well as high
  levels of IL-2.

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Mechanism of action

• Suppress T-cell proliferation via rapid secretion
  of IL-10 and TGF-b. Suppression is reversed by
  neutralizing abs.
• Suppression of immunoglobulin by B cells.
• TCR ligation is essential for suppression.
• Suppression is more efficient with cell contact
  and may be antigen non-specific.

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Th3 cells

• TGF-b secreting cells in Peyers patches 24-48
  hrs after low dose feeding of self Ag.

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(Intraepithelial lymphocyte)
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Figure 13-16
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The role of costimulation in T-cell suppression
(1)
CTLA-4-CD80/86
Treg
Teff
TCR-Ag
APC
TCR-Ag
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Costimulation 2.
CTLA-4-CD80/86
Treg
Teff
TCR-Ag
TCR-Ag
APC
IDO
Tryptophan
IDO-indoleamine 2,3-dioxygenase
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Costimulation 3.
CTLA-4-CD80/86
CD80/86- CTLA-4
Teff
Teff
TCR-Ag
APC
TCR-Ag