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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

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Presentation Transcript
slide2

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
slide3

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

slide5

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

slide6

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

slide7

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
slide8

The plasticity of Smad proteins in transcriptional regulation and the diversity of Smad-independent pathways enable TGF-β to exert its pleiotropic actions

slide9

TGF-β Regulates T Cell Development

  • Using different mice models (TGF-βRII- and TGF-βRI-deficient mice, TGF-βRII-deficient 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
slide10

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 non-self 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
slide11

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)

slide12

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
slide13

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?

slide14

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

slide15

T cells

Foxp3 expression

induced Treg (iTreg) cells in periphery

thymic nTreg cells

TGF-β

  • 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

slide16

T cells

RORγt expression

Foxp3 expression

Th17 cells

induced Treg (iTreg) cells in periphery

thymic nTreg cells

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

slide17

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

slide19

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
slide20

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