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Naive CD4 T

Not produce classical Th1 /Th2 cytokines Low levels GATA-3/T-bet IL-4/IFN γ supress differentiation. Th 17. Th 1. IL-21. IL-12. + IL-1. TGF β. IFN γ. ROR γ t. T-bet. IL-6. Naive CD4 T. IL-23. IL-4. GATA-3. Foxp3. TGF β. IL-2. iTreg. Th 2. IL-4. TGF β. A little history

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Naive CD4 T

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  1. Not produce classical Th1/Th2 cytokines • Low levels GATA-3/T-bet • IL-4/IFNγ supress differentiation Th 17 Th 1 IL-21 IL-12 + IL-1 TGFβ IFNγ RORγt T-bet IL-6 Naive CD4 T IL-23 IL-4 GATA-3 Foxp3 TGFβ IL-2 iTreg Th 2 IL-4 TGFβ A little history 15.02.2010

  2. Extracellular bacteria Fungi Autoimmunity Intracellular pathogens Autoimmunity IL-22 IL-2 IL-17a IFNγ Th 17 Th 1 IL-17f LTα IL-21 IL-12 + IL-1 TGFβ (IL-10) IFNγ (IL-10) RORγt/Stat3 T-bet/Stat4 IL-21 IL-6 Naive CD4 T IL-23 IL-4 GATA-3/Stat5 Foxp3/Stat5 TGFβ + IL-2 IL-2 IL-13 IL-35 iTreg Th 2 IL-4 IL-10 IL-5 Immune tolerance Lymphocyte homeostasis Regulation of immune responses Extracellular pathogens Allergy and asthma Amphiregulin TGFβ IL-25 IL-10 A little history 15.02.2010 Factors of differentiation Produced cytokines Transcription factors

  3. Cytokines

  4. Intracellular pathogens (Mycobacteria) Autoimmunity IFNγ Th 1 Activate macrophages to increase their microbicidal activity LTα Mediates variety of inflammatory, immunostimulatory, and antiviral responses IL-2 CD4 cell memory (critical for CD8 memory formation) The cells: cytokine produced and functions 15.02.2010

  5. mucin Eosinophil serotonin IL-4 IL-13 TNF-α Recruits eosinophils histamine Epithelialcell lymphocyte IL-5 Expulsion of helmints Airway hypersensitivity Mast cell Mast cell Basophil IL-13 Recruits mast cells and lymphocytes Induces mucin production IL-9 FcЄRI FcЄRI Major mediator for IgE in B cells Th 1 Supression of Th1 IL-10 IL-4 Supression of dendritic cells function Dendriticcell Positive feedback for Th2 differentiation Th 2 Amphiregulin Epithelialcell Induces epithelial cells proliferation IL-25 Naive CD4 T IL-4 IL-17B CCL5 CCL11 IL-5 Extracellular pathogens (helmints) Allergy and asthma Enhances IL-4 and IL-5 production Recruits eosinophils Eosinophil

  6. Naive CD4 T Induction of chemokines Induction of inflammatory cytokines IL-6 IL-8 Inflammatory responses Th 17 IL-17a LCR Neutrophil Higher affinity Recruit and activate nuetrophils IL-17A IL-17f IL-6/IL-23 Stat 6 Dendriticcell CD8 T IL-21 Positive feedback amplifier Acts on CD8, B cells, NK and Dendritic cells NK IL-22 B cell Mediates dermal inflammation Prtotects hepatocytes during acute liver inflammation Mediates host defence against bacteria (Klebsiella pneumoniae and Citrobacter rodentium) Extracellular bacteria Fungi Autoimmunity The cells: cytokine produced and functions 15.02.2010

  7. Immune tolerance Lymphocyte homeostasis Regulation of immune responses IL-10 Negative regulatory mechanism for limmiting immune responses to prevent host tissue damage Mediates supression in some cases Prevention and cure of inflammatory bowel disease Limits the severity of EAE (experimental autoimmune encephalomyelitis) Stimulation of protective immunity during the pathogen persistence TGFβ IL-35 Treg Supressive activity The cells: cytokine produced and functions 15.02.2010

  8. Receptors

  9. IL-18Rα IL-12Rβ1 ! IL-1R1 IL-23R IL-18Rα IL-12Rβ2 TCR activation Th 17 Th 1 IL-12 IFNγ CCR5 CCR6 CCR4 CXCR3 Naive CD4 T IL-2Rα (CD25) IL-2Rα (CD25) CTLA-4 IL-4 IL-4α IL-33Rα (T1/ST2) ! IL-2 IL-2 GITR iTreg Th 2 CD103 Folr4 CRTh2 CCR3 CCR8 CCR4 Expression of cytokine and chemokine receptors by Th cells 15.02.2010

  10. Transcriptional Factors Transcriptional factors critical for each T helper lineage 15.02.2010

  11. Stat4 Th17 differentiation Transcriptional repressor during CD8 development IFNγ IL-12 RORγt Runx3 NF-κB inducer Th 17 Th 1 IRF4 RORα Stat1 IFNγ mediated Induction of T-bet RORγt expression T-bet Stat3 Stat4 IL-21 Th1 master regulator Major signal trancducer for IL-21, IL-23, IL-21 IL-6 IL-12 signal transducer Indice IFNγ production in activated CD4 cells Naive CD4 T IL-23 Induction of IL-23R TGFβ Cytokine driven proliferation and cell survival Maintaines suppressive sctivity IL-4 IL-2 Stat5a/Stat5b Foxp3 IL-2 iTreg Th 2 Major signal trancducer during IL-4 mediated Th2 differentiation Stat6 c-Maf Stat5 Enhances IL-4 production Th2 differentiation Th2 master regulator GATA-3 Gfi-1 Treg development Foxp3 induction Modulates IL-2 signals Transcriptional factors critical for each T helper lineage 15.02.2010

  12. T helper differentiation T helper differentiation 15.02.2010

  13. Naive CD4 T Naive CD4 T Dendriticcell Naive CD4 T IL-12 Stat1 NK T-bet IFNγ Naive CD4 T Selection IFNγ IL-12Rβ2 IL-12 IL-12Rβ1 IL-18Rα IL-12Rβ2 Stat4 Naive CD4 T Th 1 IL-2 LTα IFNγ (IL-10) CCR5 IL-18Rα CXCR3 Naive CD4 T IL-12 T-bet/Stat4 Stat4 IFNγ Naive CD4 T IL-18 IL-12Rβ2 (sustains) IL-12 IFNγ IL-12Rβ2 T helper differentiation Th1 cell differentiation 15.02.2010

  14. GATA-3 IL-4 exogenous IL-2 GATA-3 GATA-3 Naive CD4 T Naive CD4 T Naive CD4 T Stat6 Stat6 selects Naive CD4 T Naive CD4 T Naive CD4 T Gfi-1 Transcriptional repressor GATA-3 GATA-3 Naive CD4 T IL-4 IL-4 Naive CD4 T GATA-3 IL-2 IL-2Rα (CD25) Naive CD4 T IL-4α IL-33Rα (T1/ST2) IL-25 IL-13 Th 2 Stat5 IL-4 Amphiregulin GATA-3 IL-5 Stat5 Il4/Il13 CRTh2 IL-10 Va Csn HSII HSIII CCR3 CCR8 CCR4 Naive CD4 T T helper differentiation Th2 cell differentiation 15.02.2010

  15. Cells of innate immuntiy Naive CD4 T IL-6 IL-18Rα IL-1R1 IL-23R TGFβ Th 17 IL-17a IL-22 Naive CD4 T Naive CD4 T IL-17f IL-21 IL-23 IL-23 (IL-10) CCR6 RORγt RORγt IL-21 IL-21 CCR4 Stat3 IL-23 IL-6 IL-21 T helper differentiation Th17 cell differentiation 15.02.2010

  16. TGFβ Smad3 Naive CD4 T IL-2Rα (CD25) NFAT CTLA-4 IL-10 foxp3 GITR iTreg IL-2 Naive CD4 T CD103 Folr4 TGFβ IL-35 Foxp3 TGFβ Stat5 Naive CD4 T IL-2 T helper differentiation Treg cell differentiation 15.02.2010

  17. Cross-regulation of differentiation • Levels of cross-regulation: • By cytokines • Transcriptional regulation of critical factors • Cytokine transcription Cross-regulation of T helper differentiation 15.02.2010

  18. Treg Th17 Th2 Th1 IL-2 IL-17 TGFβ TGFβ IL-4 IFNγ Stat5 Stat4 RORγt RORγt GATA-3 T-bet Foxp3 Stat3 Gfi-1 Runx3 Cross-regulation of T helper differentiation 15.02.2010

  19. Epigenetic changes in Th differentiation Epigenetic changes in Th differentiation 15.02.2010

  20. Epigenetic changes in Th differentiation 15.02.2010

  21. Immunologic abnormalities Immunologic abnormalities resulting from mutations or polymorphisms in the pathways of Th differentiation 15.02.2010

  22. Th 17 Stat3 Susceptibility to some bacterial infections Inability to develop Th17 Treg IPEX syndrome (immunodysregulation, polyendocrinopathy, enteropathy, x-linked) Inability to develop Treg Foxp3 IL2RA IPEX like syndrome Th 2 GATA-3 HDR syndrome (hypoparathyroidism, sensorineural deafness, renal dyplasia) Differentiation into Th2 is diminished Th 1 T-bet Asthma and airway hyperresponsiveness Immunologic abnormalities resulting from mutations or polymorphisms in the pathways of Th differentiation 15.02.2010

  23. Thank You

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