Negative regulation of immune responses by various mechanisms

Negative regulation of immune responses by various mechanisms

NEGATIVE REGULATION OF T CCELL RESPONSES

Days5 10 15 20 25 30

Naive lymphocytes

Number of antigen specific cells

Primary effectors

Secondary effectors

Memory

DIFFERENTIATION

AICD

EXPANSION

AICD

MEMORY

AICDActivation Induced Cell Death

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 DEATHExpression 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

C D 8 + Tc

F a s

C D 4 + T h 1

F a s L

C D 4 +

T h 1

A P C

B

THE ROLE OF CD4+ T CELLS IN APOPTOSISFas receptor – Fas ligand interactions

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

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 FailureAbbas, 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.

Anergy

CD28

Activated T cell

CD28 cross linked by B7

Costimulatory molecules associatealso with inhibitory receptors

CTLA-4 binds CD28 with a higher affinity than B7 molecules

/CTLA-4

B7

CD28

T cell

B7

2 2Signal 1 +

Co-stimulation induces CTLA-4DELAYED EXPRESSION

The lack of signal 2 to the T cell shuts down the T cell response

Cross-linking of CTLA-4by B7 inhibits co-stimulationand inhibits T cell activation

- - -- -

B71/2

TAPC

CD28 activation

CTLA-4

ITIM

NEGATIVE REGULATION OF T CELL ACTIVATION BY 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


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 FailureAbbas, 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.

Regulatory T cells develop in the tymus(Natural Tregs, Sakaguchi)

Development of the CD25+CD4+ Development of the CD25+CD4+ regulatory T cell lineageregulatory T cell lineage

TCR as polymorphic as for CD25- cellsTCR as polymorphic as for CD25- cellsSpecific to self antigens, MHC II restrictedSpecific to self antigens, MHC II restrictedRequires IL-2, Requires IL-2, Co-stimulation, CD28, B7Co-stimulation, CD28, B7

Foxp3 is a master regulatorFoxp3 is a master regulatortransforms CD25 statustransforms CD25 status

SchwartzSchwartzNat Immunol Nat Immunol 20052005

Hassall’s corpuscles instruct dendritic cells to induce Hassall’s corpuscles instruct dendritic cells to induce CD4+CD25+ regulatory T cells in human thymusCD4+CD25+ regulatory T cells in human thymus

TSLP:TSLP: Thymic stromal lymphopoietin (activates human DC) Thymic stromal lymphopoietin (activates human DC)DC-LAMP:DC-LAMP: Dendritic cell lysosomal-associated Dendritic cell lysosomal-associated membrane proteinmembrane protein Watanabe et al. Nature 436, 1181Watanabe et al. Nature 436, 1181

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.

I

Natural and induced Tregs

nTregnTreg

THYMUSTHYMUS

PERIFÉRIAPERIFÉRIAFoxP3+

FoxP3-

IL-2/TGFβ MaintenanceMaintenance

nTregnTreg

Effector T

IL-10/IL-35/TGFβSupressionSupression

Effector T

DC

FoxP3-Tr1Tr1

IL-10/ TGFβ

IL-10

SuppressionSuppression SuppressionSuppression

FoxP3+Th3Th3

TGFβ

IL-10/ TGFβ

mTEC

CD4+TCD4+TFoxP3-

iTregiTreg

FoxP3+

PERIPHERYPERIPHERY

ORIGIN, TYPES AND FUNCTIONS OF REGULATORY T CELLSORIGIN, TYPES AND FUNCTIONS OF REGULATORY T CELLS

FUNCTIONS OF REGULATORY T CELLSFUNCTIONS 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

REGULATORY T CELLSREGULATORY T CELLS

Homeostatic regulationHomeostatic regulation

THYMUSTHYMUS

Natural– nTregNatural– nTreg

PERIPHERYPERIPHERY

Induced – iTregInduced – iTreg

Induced regulationInduced regulationTregTreg

Autoimmune diseasesAutoimmune diseases Transplantation toleranceTransplantation tolerance

Malignant diseasesMalignant diseases

DCDC

AKTIVATIONAKTIVATION INDUCTIONINDUCTION

COLLABORATION OF REGULATPRY T-LYMPHOCYTES AND COLLABORATION OF REGULATPRY T-LYMPHOCYTES AND DENDRITIC CELLS DENDRITIC CELLS

TregTregCD25IL-2Rα

CTLA4B7 ligand

GITR

MARKERS OF THYMUS DERIVED NATURAL Treg CELLS

CD127IL-7Rα ↓

Treg differentiation, maintenance, functionTranscription factor – many target genesFoxP3 by itself is not sufficient to confer suppressive functionsTGFβ does not induce regulatory functions

FoxP3

CD4+CD25+FOXP3+

REGULATORY T CELLS

MECHANISMS RELATED TO REGULATORY T LYMPHOCYTE MECHANISMS RELATED TO REGULATORY T LYMPHOCYTE FUNCTIONSFUNCTIONS

IL-35

Inhibitory cytokines

TGFβ

IL-10

Cytolysis

Metabolic disturbance Inhibition of dendritic cell differentiation

Reduced cytokine production (IL-2)Reduced cytokine production (IL-2)Peri-cellular adenosinePeri-cellular adenosine

cAMP transfercAMP transfer

Indolamine-2,3 dioxigenaseIndolamine-2,3 dioxigenaseLAG-3 – CD4 homologueLAG-3 – CD4 homologue

CELL SURFACE ENZYMES OF REGULATORY T CELLS CELL SURFACE ENZYMES OF REGULATORY T CELLS PRODUCE EXTRACELLULAR NUCLEOTIDESPRODUCE EXTRACELLULAR NUCLEOTIDES

Ectonucleoside triphosphate diphosphohydrolase (E-NTPDase

Ecto-5’-nucleotidase

EBI3Ebstein-Barr virus induced gene 3

IL-27 and IL-35

Naiv T sejtek toborzása, aktiválása, polarizálása

CD4+CD25- effektor sejtek A2A receptort fejeznek ki

Peri-cellular/Szupresszív


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 regulates Treg functions through inhibiting CD80 and CD86 mediated co-stimulatory signals resulting in reduced inflammatory cytokine production. CTLA-4 also induces indoleamine-2,3-dioxygenase (IDO) enzyme activity that has immune suppressive effects.

CTLA-4 is an important membrane protein that through Treg cell can regulate antigen presenting cell functions

Blocking CTLA-4 tissue specific autoimmune disease, inflammatory bowel disease (IBD) in mice.

•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

A klinikai alkalmazás lehetőségei:


TregTreg

RESTING Foxp3+ Treg

THYMUSTHYMUS

nTreg

PERIPHERYPERIPHERY

iTregiTreg

ACTIVATED Foxp3+ Treg

Local effectsLocal effectsPAMP, TLR, NLR, RLRPAMP, TLR, NLR, RLRInflammation, IFN, TGFInflammation, IFN, TGFββT cell activationT cell activation

Treg activationCTLA4, GITR, IL-10, CTLA4, GITR, IL-10,

IDO, PD-1/PD-LIDO, PD-1/PD-L

TregTreg TregTreg

TOLEROGENIC RESPONSE HELPER RESPONSE

Local tolerance Local immune response

Treg re-programingIL-6, IL-1IL-6, IL-1

DEVELOPMENT OF REGULATORY T LYMPHOCYTES IS DEVELOPMENT OF REGULATORY T LYMPHOCYTES IS ENVIRONMENT DEPENDENTENVIRONMENT DEPENDENT











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Negative regulation of immune responses by various mechanisms