regulation of immune response by cytokines

1. Regulation of immune responses by
cytokines (TGF-BETA, IL -1)
Submitted by
S.Smitha
M.Sc -2nd
year
Dept of biochemistry and molecular
biology
Pondicherry University

2. CYTOKINES
• Cytokines are small secreted proteins which mediate and
regulate immunity, inflammation, and hematopoiesis. They are
produced in response to an immune stimulus.
• Cytokine is the general term for a large group of molecules
involved in signaling between cells during immune responses.
All cytokines are proteins, some with sugar molecules attached
(glycoproteines).
• They are synthesized and released by white blood cells and
tissue macrophages.
• They are proteins, peptides or glycoproteins in nature.

3. Cytokines stimulate or suppress the functional activity of lymphocytes,
monocytes, neutrophils, fibroblast and endothelial cells.
They modulate the function of other cell types. Long known to be
involved in cellular immune response, these products have additional
effects that play important roles in both acute and chronic inflammation.
Cytokines have an effect on all cells (not only on the immune cells).
Cytokines maintain a rigidly controlled communication network between
the individual cell types including those of the nervous system.
Cytokines are released in the course of normal cell functions, especially
in response to particular stimulus: e.g. antigens, immune complexes,
complement, enzymes, other cytokines.

4. TRANSFORMING GROWTH FACTOR BETA
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

5. 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

6. regulation of T cells by TGF-β

7. 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

8. 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

9. -
-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

10. 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

11. TGF-β regulates naive T cell homeostasis
• 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
TGF-β signalling in T cells is essential for maintaince of peripheral T cell
tolerance

12. 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
TGF-β-deficient mice with other single nonself TCR affinities (TEα transgenic T cells and
DO11.10 T cells)
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

13. • 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

14. • 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

15. 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

16. TGF-β engages multiple signalling pathways to control T cell development

17. 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

18. interleukin-1
A soluble protein (17 kD: 152 amino acids) secreted by
monocytes, macrophages or accessory cells involved in the
activation of both T-lymphocytes and B lymphocytes and
potentiates their response to antigens or mitogens.
It is released early in an immune system response by
monocytes and macrophages. It stimulates T-cell proliferation and
protein synthesis. Another effect of IL-1 is that it causes fever.
The principal function of IL-1 is as a mediator of the host
inflammatory response to infections & other inflammatory stimuli.

19. Sources of IL-1
• Major sources
 Mononuclear phagocytes(induced by bacterial
products and by other cytokines )
 Neutrophils
 Epithelial cells &
 Endothelial cells
• Non major source
 Platelets, NK cells,Kidney mesangial cells
 Langerhans cells,Dermal dendritic cells
 Maternal placenta cells.

20. INTERLEUKIN-1∝
 Interleukin-1 alpha (IL-1α) is a protein that in humans
is encoded by the IL1A gene.
 The protein encoded by this gene is a cytokine of the
interleukin-1 family.
 Interleukin-1 alpha possesses a wide spectrum of
1. metabolic,
2. physiological,
3. haematopoietic activities,
4. and plays one of the central roles in the regulation of
the immune responses. It binds to the interleukin-1
receptor.

21. INTERLEUKIN-1β
• Interleukin-1 beta (IL-1β) also known as
catabolin.
• The active form of IL-1ß is a cleaved
product.
• IL-1β precursor is cleaved by caspase 1
(interleukin 1 beta convertase) to generate
the biologically active secreted protein.

22. The interleukin-1 receptor
 The interleukin-1 receptor antagonist (IL-1RA) is a
protein that in humans is encoded by the IL1RN gene.
 IL-1RA was initially called the IL-1 inhibitor
 IL-1RA, is an agent that binds to the cell surface
interleukin-1 receptor (IL-1R).
 Hence IL-1RA prevents IL-1 from sending a signal to that
cell.

23.  Type I receptor:
•It is expressed on almost all cell type & major
receptor for IL-1 mediated responses.
•The IL-1 receptor accessory protein (IL1RAP)
is a transmembrane protein that interacts with
IL-1R and is required for IL-1 signal
transduction.
Type II receptor:
•it is expressed on B cells & may be induced on
other cell types.
•Act as a suppressor of IL-1 activity by
competing for IL-1 binding.

24.  Binding of IL-1 to the type 1 IL-1Receptor
leads to- the activation of the NF-қB & AP-
1 transcription factors by a signaling
pathway that appears to involve a member
of the TRAF family.

25. Summary
 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
TGF-β:

26. IL-1
• IL-1α and IL-1β bind to the same receptor molecule, which is called
type I IL-1 receptor (IL-1RI). There is a third ligand of this receptor –
the Interleukin 1 receptor antagonist (IL-1Ra), which does not
activate downstream signaling, so it acts as one of the control
mechanisms of IL-1α and IL-1β signaling by competing with them
about binding sites of thereceptor.
• Interleukin 1 binds to the il 1 receptor, it leads to the regulation of
immune response...
• Binding of IL-1 to the type 1 IL-1Receptor leads to- the activation of
the NF-қB & AP-1 transcription factors by a signaling pathway that
appears to involve a member of the TRAF family.