Transcript T cells
Evgeniya Solodova 01.12.08 Introduction: Regulatory cytokine transforming growth factor-β (TGF-β): - is a secreted protein that exists in three isoforms called TGF-β1, TGF-β2 and TGF-β3 - TGF-β1 is the founding and predominant member of this family - controls proliferation, differentiation, and other functions in many cell types - acts as a negative autocrine growth factor - specific receptors for TGF-β activation trigger apoptosis when activated - many cells synthesize TGF-β and almost all of them have specific receptors for this peptide Introduction: T lymphocytes are the key components of the adaptive immune system - express T cell receptors (TCR) which recognize antigens in association with molecules of MHC - selected in the thymus according to the affinity to self-antigens to prevent auto immune response - differentiate upon infection into effector T cells – CD4+ helper T cells or CD8+ cytotoxic T cells – to combat the invading pathogen All these crucial processes of T cell development, homeostasis, tolerance to self antigens and differentiation are highly dependent on TGF-β regulation Understand the regulation of T cells by TGF-β Synthesized in inactive form in association with latency-associated protein (LAP) Secreted as such Bind to latent-TGF-β-binding protein (LTBP) targeting TGF-β to ECM cells that produce TGF-β activator can differ from those that secrete TGF-β integration of signals from multiple cell types to regulate cellular responses - Binding to complex of TGF-β type I (TGF-βRI) and type II (TGF-βRII) receptors active signalling pathways - Phosphrilation of transcriptional factors Smad2 and 3 translocation to the nucleus with Smad4 or TIF1γ - Binding to the regulatory sequences in target genes regulation of gene expression OR - Activation of Smad-independent signalling pathways The plasticity of Smad proteins in transcriptional regulation and the diversity of Smad-independent pathways enable TGF-β to exert its pleiotropic actions TGF-β Regulates T Cell Development Using different mice models (TGF-βRII- and TGF-βRI-deficient mice, TGF-βRIIdeficient H-Y TCR transgenic mice) it was shown that TGF-β signalling in T cells : - promotes CD8+ and CD1d-dependent natural killer (NKT) T cell differentiation - reveals opposing functions on the CD4+Foxp3+ regulatory T (nTreg) cell development depending on the mice age TGF-β regulates naive T cell homeostasis TGF-β signalling in T cells is essential for maintaince of peripheral T cell tolerance - How TCR specificity modulates T cell responses in TGF-β-deficient mice or mice with T cell-specific inactivation of TGF-β receptors? - What is the reason for naive T cell loss when TGF-β signalling is disrupted? • TGF-βRII-deficient OT-II cells (T cell TCRs have high binding affinity only to nonself MHC II antigen) undergo a high cell death and are largerly depleted in peripheral lymphoid organs • Lack of TGF-β signalling in CD8+ cells in H-Y TCR-transgenic mice led to diminished mature T cell numbers in female mice TGF-β regulates naive T cell homeostasis In OT-II mice, deficient for Tgfbr2 gene, T cells actively differentiate into T helper 1 (Th1) or Th2 effector T cells, in contrast to normal polyclonal T cell population Th1 cells secrete IFNγ and lymphotoxin to combat intracellular pathogens through activation of adaptive immune system Th2 cells produce IL-4, IL-5 and IL-13 which direct antibody production to control extracellular pathogens TGF-β-deficient mice with other single nonself TCR affinities (TEα transgenic T cells and DO11.10 T cells) • TGF-β may have an essential role in promoting the survival of both CD4+ and CD8+ naïve T cells that interact with low affinity to self-antigens • Modulates immune tolerance by inhibiting high-affinity CD4+ and CD8+ T cell proliferation and differentiation into Th1 and Th2 and cytotoxic T lymphocytes • Active immune suppression by cytokine TGF-β1 or CD4+Foxp3+ Treg cells is a pivotal mechanism of peripheral T cell tolerance • Mice lacking either TGF-β1 or Foxp3, the transcription factor required for Treg cell function, develop multifocal inflammatory disorders What is the mechanism underlying TGF-β regulation of T cell tolerance? TGF-βRII-, TGF-β1-deficient mice, bone marrow chimera and T cell transfer experiments Lack of TGF-β signalling leads to: -Reduction of nTreg cell -More activated and differentiated phenotype of T cell populations T cells Foxp3 expression thymic nTreg cells induced Treg (iTreg) cells in periphery • recruiment of downstream transcriptional factor Smad3 to a Foxp3 enhancer element • T cell produced IL-2 activates STAT5 for binding to Foxp3 promoter Differentiation of iTreg cells TGF-β RORγt expression T cells Foxp3 expression Th17 cells thymic nTreg cells induced Treg (iTreg) cells in periphery TGF-β • recruitment of downstream transcriptional factor Smad3 to a Foxp3 enhancer element • T cell produced IL-2 activates STAT5 for binding to Foxp3 promoter Differentiation of iTreg cells • IL-6 activates STAT3 induction of ROPγt expression Differentiation of Th17 cells • Foxp3 interacts with ROPγt and suppresses its function mechanism for reciprocal differentiation of iTreg and Th17 cells Th17 cells secrete IL-17A, IL-17F, IL-22, that act on a broad range of innate immune and nonhematopoietic cells to protect the host from extracellular pathogens RORγt - transcription factor that orchestrates the differentiation of Th17 lineage TGF-β inhibits Th1, Th2 and CTL proliferation and differentiation TGF-β • Block of TCR-induced Tec kinase Itk activation and Ca2+ influx in T cells • Downregulation of NFAT, T-bet and GATA-3 expression • Inhibition of IL-2, IFNγ and granzyme B transcription via association of TGF-β with Smad2/3 complexes Inhibition of Th1, Th2 and CTL cell proliferation and differentiation Itk kinase - Interleukin-2 inducible T-cell protein tyrosine kinase NFAT - Nuclear factor of activated T-cells Th1 - specific T box transcription factor granzyme B - granzyme 2, cytotoxic T-lymphocyte-associated serine esterase 1 TGF-β engages multiple signalling pathways to control T cell development A Three-Cell Model for TGF-β1-Dependent Regulation of T cells • Antigen recognition and presentation by DCs • Activation of Treg cells • Production of latent form of TGF-β1 • Association with LAP (and LTBP) • Activation and release of TGF-β1 • Inhibition of CD4+ T cell differentiation into Th1 and Th2 cells • Promotion of CD4+ T cell differentiation into iTreg or Th17 cells • Low production of TGF-β1 by activated CD4+ T cells that potentially regulates T cell differentiation through an autocrine route Summary and Future Perspectives TGF-β: regulates thymic T cell development and peripheral T cell survival, proliferation and differentiation ensures the maintenance of divers and self-tolerant T cell repertoire and the initiation of appropriate T cell responses essential for an effective adaptive immune system may have an important role in more ancient biological processes such as embryonic development and carcinogenesis New insights into the control of T cell responses by TGF-β will help to illuminate the fundamental principles of T cell regulation and facilitate the employment of TGF-β to treat a variety of immune-related disorders Thank you for your attention!