A detailed description of the nature, types, and mechanisms of action of cytokine receptors. Describes the different functions of cytokines and their role in the regulation of the immune response. Cytokine receptor signalling and their regulation and the role of cytokines in disease is also covered briefly.

1. Cytokine Receptors
Mohammad Mufarreh

2. Cytokine -mediated effects
• Cell growth.
• Cell differentiation.
• Cell death.
• Induce non-responsiveness to other
cytokines/cells.
• Induce responsiveness to other
cytokines/cells.
• Induce secretion of other cytokines.

3. How do cytokines tell cells what to do?
• Produced by cells as part of normal
cellular activity and/or the result of
environmental trigger.
• Cytokines are not specific to antigens.
• Bind to receptors on cells.
• Trigger signal transduction pathways.
• Initiate synthesis of new proteins.

4. Cytokine Receptors
• Cytokine receptors are receptors that
bind cytokines.
• Binding to specific receptors is essential
for cytokines to carry out their
functions.
• Cytokine receptors may be both
membrane-bound and soluble.
• Soluble cytokine receptors are
extremely common regulators of
cytokine function.

6. Cytokine Receptors

7. Cytokine Receptors

8. Cytokine Receptors

9. Cytokine Receptors

10. Cytokine Receptors

11. Cytokine Receptors

12. Cytokine Receptors
TGF-beta Receptors
TGF-beta Receptor 1
TGF-beta Receptor 2

14. 3 Subfamilies of Class I Cytokine Receptors

17. Type I cytokines whose receptor share c chain
IL-2 receptor family (common
c
chain, CD132)
heterodimerics
IL-2
IL15
IL-4
(IL-7( , c); IL-9 ( , c) IL-21 ( , c)

18. Interactions between Cytokine-specific Subunits
and a Common Signal-transducing Subunit of
Cytokine Receptors.

19. Interactions between Cytokine-specific Subunits
and a Common Signal-transducing Subunit of
Cytokine Receptors.

20. Competition of Ligand-binding Chains of
Different Receptors for a Common Subunit
Can Produce Antagnistic Effects between
Cytokines.

21. 3 Forms of the IL-2 Receptor
(CD25)

22. 3 Forms of the IL-2 Receptor
Intermediate affinity
Expression:
NK cells
Resting TC
High affinity
Low affinity
IL-2Ra, CD25
Activated
CD4+,
CD8+ Tc
Resting
CD4+TC
B cells
CD8+Tc
Signal Transduction:
and chains

23. JAK-STAT Signal Transduction Pathways
of Cytokine Receptors
• JAK: Janus kinases. (or Just Another
Kinase).
• STAT: Signal Transducers and Activators
of Transcription.

24. JAK-STAT Signaling Pathway

25. JAK-STAT Signaling Pathway

26. JAK-STAT Signaling Pathway

27. JAK-STAT Signaling Pathway

28. The Regulation of Th Subsets by Cytokines

29. Transcription Factors: Th1 vs. Th2

30. Seven-transmembrane-domain receptors signal
by coupling with trimeric GTP-binding
proteins

31. Other signaling pathways

32. Suppressor Of Cytokine Signaling (SOCS) target
Jaks to downregulate signaling
cytokine inducible family of genes which function
as feedback inhibitors of signaling.

34. Cytokine receptors in disease
• Hyperactivating mutations affecting type I
cytokine receptor signaling pathway are found
associated with several myeloproliferative
diseases.
• Inappropriate activation of type I cytokine
receptor signaling appears to be a hallmark of a
range of malignancies, including leukemias and
lymphomas.
• Defects in signaling by members of the IL-2
receptor family cause the majority of cases of
severe combined immune deficiency (SCID).

35. Cytokine and cytokine receptor polymorphisms in
infectious disease
• The capacity of monocytes to produce TNFα
varies more than tenfold between individuals.
• Several polymorphisms within the TNFα gene
have been associated with increased TNFα
production and increased mortality of sepsis.
• However, these associations most likely result
from linkage disequilibrium with other
immune response genes on chromosome 6.
• Polymorphisms within the IL-1β and the IL-1RA
genes (located on chromosome 2) have been
linked to inflammatory disease (e.g. Rheumatoid
arthritis).

36. Cytokine and cytokine receptor polymorphisms in
infectious disease
• Mutations in the receptors for IL-12 and IFNγ,
both critical for clearance of intracellular
infectious pathogens, are associated with severe
recurrent infections with Salmonella species
and mycobacteria.
• TNFR1 mutations cause fever of unknown
origin.

37. Impaired cytokine signaling in human disease
• Constitutive activation of Jak/Stat pathway in
leukemia, HTLV1 transformed cells.
• Jak2 inhibitor as a therapeutic agent.
• SCID families exhibit abnormalities in
lymphocyte-specific Jak3 gene.
• The same phenotype is observed in individuals
with mutations in the receptor component which
associates with Jak3.
• Constitutively active STATs (usually stat3) in
human cancers.
• Defects in IFNγ signaling in lung cancer.
• General role of IFNγ in tumor surveillance.