Transcript Document

Introduction to Autoimmunity
Alon Monsonego, Ph.D.
The department of Microbiology and Immunology
Tel: 08-647-9052
Topics:
• T-cell selection
• T-cell activation
• T-cell regulation
The Development and
Survival of Lymphocytes
The development of T cells:
Figure 7-2 part 1 of 2
Figure 7-2 part 2 of 2
The cellular organization of the human Thymus:
Figure 7-8 part 1 of 2
Figure 7-9
The thymus is critical for T-cell maturation:
Figure 7-10
Changes in cell surface molecules throughout T-cell maturation in the
Thymus:
Figure 7-12
Figure 7-14
Positive selection in the thymus:
Figure 7-32 part 1 of 2
Figure 7-32 part 2 of 2
Negative selection in the thymus by bone marrow derived cells:
Figure 7-35
Figure 7-36
Expression of AIRE in the thymus shape the immune
repertoire:
Figure 13-9
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
T Cell-Mediated Immunity
Distribution of APCs in the lymph nodes:
Figure 8-3
dictate
Naïve T cells encounter antigen in the peripheral lymph node:
Figure 8-4
Two signals are required to induce T-cell activation:
Figure 8-13
DC’s maturation as APCs:
Figure 8-14
Figure 8-15
T-cell tolerance to antigens expressed on tissue cells:
Figure 8-21
Activation of CD4 T cells:
Figure 8-24
Effector T cells with different functions:
Figure 8-31
T-cell cytokines:
Figure 8-32 part 1 of 3
Figure 8-32 part 2 of 3
Figure 8-32 part 3 of 3
Molecular differentiation of Th1,Th2, and
Th17 T cells
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.
Mechanisms of autoimmune
diseases
Figure 13-1
Figure 13-6
Figure 13-31
T-cell mediated paralysis in a mouse model of multiple sclerosis:
Figure 13-3
Figure 13-34
Mechanisms of immune
regulation
Regulatory T cells
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.
Figure 13-14
By stander suppression
CD4+CD25+ 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.
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.
Foxp3:
• Highly enriched in CD4+CD25+ 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 CD4+CD25- cells and lead to
expansion of CD4+CD25+ in vitro and in vivo.
• Foxp3 binds other transcrition factors such as NFAT,
AML1, RUNx1.
Different subsets of Tregs
CD4CD25
10% of CD4
A balance between regulation and
activation:
CD4CD25 regulatory T cells inhibit colitis:
Figure 13-15 part 1 of 2
Figure 13-15 part 2 of 2
Anti-ergotypic T cells:
CTLA-4-CD80/86
Treg
TCR-Ag
Teff
APC
TCR-Ag
MHC-Ag
TCR
TCR-Ag(HSP/CD25)
Terg
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.
Mechanism of action:
• Suppress T-cell proliferation via rapid secretion of IL-10 and
TGF-b. Suppression is reversed by neutralizing ab’s.
• 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.
Th3 cells:
• TGF-b secreting cells in Peyer’s
patches 24-48 hrs after low dose
feeding of self Ag.
(Intraepithelial lymphocyte)
Figure 13-16
The role of costimulation in T-cell suppression
(1)
CTLA-4-CD80/86
Treg
TCR-Ag
Teff
APC
TCR-Ag
Costimulation 2.
Treg
CTLA-4-CD80/86
TCR-Ag
Teff
APC
IDO
IDO-indoleamine 2,3-dioxygenase
TCR-Ag
Tryptophan
Costimulation 3.
CTLA-4-CD80/86
Teff
TCR-Ag
CD80/86- CTLA-4
APC
Teff
TCR-Ag