Negative regulation of immune responses by various mechanisms

NEGATIVE REGULATION OF T CCELL RESPONSES Naive lymphocytes Number of antigen specific cells Primary effectors Secondary effectors Memory DIFFERENTIATION AICD EXPANSION AICD MEMORY AICD Activation 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 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 T CELL HOMEOSTASISSHUT OFF IMMUNE RESPONSES

REGULATION OF T CELL RESPONSES BY INHIBITORY CO-RECEPTORS

A B7 : CD28 receptor family

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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, 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 associate also with inhibitory receptors CTLA-4 binds CD28 with a higher affinity than B7 molecules /CTLA-4 B7 CD28 T cell B7 22 Signal 1 + Co-stimulation induces CTLA-4 DELAYED EXPRESSION The lack of signal 2 to the T cell shuts down the T cell response Cross-linking of CTLA-4 by B7 inhibits co-stimulation and inhibits T cell activation -----

B71/2 T APC 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 ABBAS MIT 2013 Pécs

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, 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+ regulatory T cell lineage TCR as polymorphic as for CD25- cells Specific to self antigens, MHC II restricted Requires IL-2, Co-stimulation, CD28, B7 Foxp3 is a master regulator transforms CD25 status Schwartz Nat Immunol 2005

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 membrane protein Watanabe 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

nTreg THYMUS PERIFÉRIA FoxP3+ FoxP3- IL-2/TGFβ MaintenancenTreg Effector T IL-10/IL-35/TGFβSupression Effector T DC FoxP3- Tr1 IL-10/ TGFβ IL-10 Suppression Suppression FoxP3+ Th3 TGFβ IL-10/ TGFβ mTEC CD4+T FoxP3- iTreg FoxP3+ PERIPHERY ORIGIN, TYPES AND FUNCTIONS OF REGULATORY T CELLS

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

REGULATORY T CELLS Homeostatic regulation THYMUS Natural– nTreg PERIPHERY Induced – iTreg Induced regulation Treg Autoimmune diseases Transplantation tolerance Malignant diseases DC AKTIVATION INDUCTION COLLABORATION OF REGULATPRY T-LYMPHOCYTES AND DENDRITIC CELLS

Treg CD25 IL-2Rα CTLA4 B7 ligand GITR MARKERS OF THYMUS DERIVED NATURAL Treg CELLS 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 FoxP3 CD4 + CD25 + FOXP3 + REGULATORY T CELLS

MECHANISMS RELATED TO REGULATORY T LYMPHOCYTE FUNCTIONS IL-35 Inhibitory cytokines TGFβIL-10 Cytolysis Metabolic disturbanceInhibition of dendritic cell differentiation Reduced cytokine production (IL-2) Peri-cellular adenosine cAMP transfer Indolamine-2,3 dioxigenase LAG-3 – CD4 homologue

CELL SURFACE ENZYMES OF REGULATORY T CELLS PRODUCE EXTRACELLULAR NUCLEOTIDES Ectonucleoside triphosphate diphosphohydrolase (E-NTPDase Ecto-5’-nucleotidase EBI3 Ebstein-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

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Inhibition of dendritic cell functions by Treg cells Sakaguchi, Nat Immunol, 2010 In the absence of T reg 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 T reg 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:

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Treg RESTING Foxp3 + Treg THYMUS nTregPERIPHERYiTreg ACTIVATED Foxp3 + Treg Local effects PAMP, TLR, NLR, RLR Inflammation, IFN, TGFβ T cell activation Treg activation CTLA4, GITR, IL-10, IDO, PD-1/PD-L Treg Treg TOLEROGENIC RESPONSEHELPER RESPONSE Local toleranceLocal immune response Treg re-programing IL-6, IL-1 DEVELOPMENT OF REGULATORY T LYMPHOCYTES IS ENVIRONMENT DEPENDENT

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