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Negative regulation of immune
responses by various mechanisms
NEGATIVE REGULATION OF T CCELL RESPONSES
AICD
Activation Induced Cell Death
AICD
DIFFERENTIATION
Naive
lymphocytes
Memory
Primary
effectors
Number of antigen
specific cells
Secondary
effectors
EXPANSION
AICD
MEMORY
5
10
15
20
25
30
Days
Elimination of effector T cells
at the end of the immune response
Activation-induced cell death (AICD)
Sustained T cell activation induces pro-apoptotic signals
Expression of Fas, FasL, Bad, Bax is increased – CELL DEATH
Expression of Bcl-2 is decreased – SURVIVAL decreased
Signaling Pathways of AICD
Ligand binding to TNFR1 és TNFR2 receptors triggers
pro- and anti-apoptotic signalling pathways
THE ROLE OF CD4+ T CELLS IN APOPTOSIS
Fas receptor – Fas ligand interactions
4+
CD
Th1
B
CD4+
Th1
Fas L
APC
F as
C D 8+
Tc
T CELL HOMEOSTASIS
SHUT OFF IMMUNE RESPONSES
REGULATION OF T CELL RESPONSES
BY INHIBITORY CO-RECEPTORS
A B7 : CD28 receptor family
ABBAS MIT 2013 Pécs
Anergy
T cell anergy. An antigen presented by costimulator-expressing antigen-presenting cells (APCs) induces a normal T cell response. If the T cell recognizes
antigen without strong costimulation, the T cell receptors may lose their ability to deliver activating signals, or the T cell may engage inhibitory receptors, such
as cytotoxic T lymphocyte–associated protein 4 (CTLA-4), that block activation.
Immunological Tolerance and Autoimmunity : Self-Nonself Discrimination in the Immune System and Its Failure
Abbas, Abul K., MBBS, Basic Immunology: Functions and Disorders of the Immune System, Chapter 9, 171-187
Copyright © 2014 Copyright © 2014, 2011, 2009, 2006, 2004, 2001 by Saunders, an imprint of Elsevier Inc.
Costimulatory molecules associate
also with inhibitory receptors
T cell
Signal 1 +
2
2
CD28
B7
CD28 cross linked by B7
Co-stimulation induces CTLA-4
DELAYED EXPRESSION
Activated T cell
-- -- CD28/CTLA-4
B7
Cross-linking of CTLA-4
by B7 inhibits co-stimulation
and inhibits T cell activation
CTLA-4 binds CD28 with a higher affinity than B7 molecules
The lack of signal 2 to the T cell shuts down the T cell response
NEGATIVE REGULATION OF T CELL ACTIVATION BY
CTLA-4
T
APC
CD28
B71/2
activation
ITIM
CTLA-4
LATE EXPRESSION
HIGHER AFFINITY TO B7 THAN TO CD28
NEGATIVE REGULATION OF IMMUNE
RESPONSES BY REGULATORY T CELLS
The main role of regulatory T cells
ABBAS MIT 2013 Pécs
Regulatory T cells develop in the tymus
(Natural Tregs, Sakaguchi)
Central T cell tolerance. Strong recognition of self antigens by immature T cells in the thymus may lead to death of the cells (negative selection,
or deletion), or the development of regulatory T cells that enter peripheral tissues.
Immunological Tolerance and Autoimmunity : Self-Nonself Discrimination in the Immune System and Its Failure
Abbas, Abul K., MBBS, Basic Immunology: Functions and Disorders of the Immune System, Chapter 9, 171-187
Copyright © 2014 Copyright © 2014, 2011, 2009, 2006, 2004, 2001 by Saunders, an imprint of Elsevier Inc.
Development of the CD25+CD4+
regulatory T cell lineage
Schwartz
Nat Immunol
2005
TCR as polymorphic as for CD25- cells
Foxp3 is a master regulator
Specific to self antigens, MHC II restricted
transforms CD25 status
Requires IL-2,
Co-stimulation, CD28, B7
Hassall’s corpuscles instruct dendritic cells to induce
CD4+CD25+ regulatory T cells in human thymus
TSLP: Thymic stromal lymphopoietin (activates human DC)
DC-LAMP: Dendritic cell lysosomal-associated
Watanabe et al. Nature 436, 1181
membrane protein
Natural and induced Tregs
Development and function of regulatory T cells. CD4+ T cells that recognize self antigens may differentiate into regulatory cells in the thymus or peripheral
tissues, in a process that is dependent on the transcription factor FoxP3. (The larger arrow from the thymus, compared to the one from peripheral tissues,
indicates that most of these cells probably arise in the thymus.) These regulatory cells inhibit the activation of naive T cells and their differentiation into effector T
cells, by contact-dependent mechanisms or by secreting cytokines that inhibit T cell responses. The generation and maintenance of regulatory T cells also
require interleukin-2 (not shown). APC, Antigen-presenting cell.
ORIGIN, TYPES AND FUNCTIONS OF REGULATORY T CELLS
FoxP3+
PERIFÉRIA
nTreg
IL-2/TGFβ
Maintenance
mTEC
nTreg
IL-10/IL-35/TGFβ
Supression
Effector T
PERIPHERY
iTreg
FoxP3-
FoxP3-
FoxP3+
CD4+T
THYMUS
DC
IL-10
TGFβ
FoxP3+
FoxP3-
Th3
Tr1
IL-10/ TGFβ
Suppression
IL-10/ TGFβ
Effector T
Suppression
FUNCTIONS OF REGULATORY T CELLS
•Maintenance of peripheral tolerance
•Prevention of autoimmunity
•Limiting inflammatory processes (asthma, inflammatory bowel
diseases)
•Inhibit protection against infectious diseases
•Limit immune responses to tumors
MECHANISM
Intrinsic and extrinsic regulation
Various inhibitory mechanisms
Cell contacts – Cytokines
Interaction with the target effector T cells
COLLABORATION OF REGULATPRY T-LYMPHOCYTES AND
DENDRITIC CELLS
THYMUS
PERIPHERY
Natural– nTreg
Induced – iTreg
REGULATORY T CELLS
Homeostatic regulation
Treg
Induced regulation
INDUCTION
AKTIVATION
DC
Autoimmune diseases
Transplantation tolerance
Malignant diseases
REGULATORY T CELLS
MARKERS OF THYMUS DERIVED NATURAL Treg CELLS
CD4+CD25+FOXP3+
GITR
CTLA4
B7 ligand
Treg
FoxP3
CD25
IL-2Rα
CD127
IL-7Rα ↓
Treg differentiation, maintenance, function
Transcription factor – many target genes
FoxP3 by itself is not sufficient to confer suppressive functions
TGFβ does not induce regulatory functions
MECHANISMS RELATED TO REGULATORY T LYMPHOCYTE FUNCTIONS
Inhibitory cytokines
Cytolysis
TGFβ
IL-10
IL-35
Metabolic disturbance
Reduced cytokine production (IL-2)
Peri-cellular adenosine
cAMP transfer
Inhibition of dendritic cell differentiation
Indolamine-2,3 dioxigenase
LAG-3 – CD4 homologue
CELL SURFACE ENZYMES OF REGULATORY T CELLS
PRODUCE EXTRACELLULAR NUCLEOTIDES
Naiv T sejtek toborzása,
aktiválása, polarizálása
Ectonucleoside triphosphate
diphosphohydrolase (E-NTPDase
CD4+CD25- effektor sejtek A2A
receptort fejeznek ki
Peri-cellular/Szupresszív
Ecto-5’-nucleotidase
EBI3
Ebstein-Barr virus induced gene 3
IL-27 and IL-35
ABBAS MIT 2013 Pécs
Inhibition of dendritic cell functions by Treg cells
Sakaguchi,
Nat Immunol, 2010
In the absence of Treg cells the effector T-cells act as adjuvants as they
promote DC activation through increasing the expression of MHC and
co-stimulatory molecules and the production of inflammatory cytokines.
CTLA-4 is an important membrane protein that through Treg cell can
regulate antigen presenting cell functions
CTLA-4 regulates Treg
functions through
inhibiting CD80 and
CD86 mediated costimulatory signals
resulting in reduced
inflammatory cytokine
production. CTLA-4 also
induces indoleamine2,3-dioxygenase (IDO)
enzyme activity that has
immune suppressive
effects.
Blocking CTLA-4
tissue specific
autoimmune
disease,
inflammatory
bowel disease
(IBD) in mice.
A klinikai alkalmazás lehetőségei:
•A regulátor T-sejtek funkcionális aktivitásának befolyásolása komoly terápiás
Hatással lehet számos autoimmun betegség és fertőző betegség kezelése esetén
• Transzplantáció
•Tumor therapy
• How to do it? In vitro Treg expansion…. ?
•Blocking of inhibitory cell surface molecules with antibodies or otherwise
ABBAS MIT 2013 Pécs
DEVELOPMENT OF REGULATORY T LYMPHOCYTES IS
ENVIRONMENT DEPENDENT
THYMUS
PERIPHERY
nTreg
iTreg
Treg
RESTING Foxp3+ Treg
Local effects
PAMP, TLR, NLR, RLR
Inflammation, IFN, TGFβ
T cell activation
ACTIVATED Foxp3+ Treg
Treg activation
CTLA4, GITR, IL-10,
IDO, PD-1/PD-L
Treg
Local tolerance
TOLEROGENIC RESPONSE
Treg re-programing
IL-6, IL-1
Treg
Local immune response
HELPER RESPONSE
ABBAS MIT 2013 Pécs
ABBAS MIT 2013 Pécs
ABBAS MIT 2013 Pécs
ABBAS MIT 2013 Pécs
ABBAS MIT 2013 Pécs
ABBAS MIT 2013 Pécs
ABBAS MIT 2013 Pécs
ABBAS MIT 2013 Pécs
ABBAS MIT 2013 Pécs
ABBAS MIT 2013 Pécs