9. Cytokine families
• Six cytokine families
– IL-1 family
– Hematopoietin (Class I) family
– Interferon (Class II) family
– TNF family
– IL-17 family
– Chemokine family
10.
11. Cells That Make Cytokines And Their
Function
• A Variety Of Cells Are Capable Of Making
Cytokines
• However The Biggest Producers: M and TH
• Cytokines Are Involved In
– Hematopoiesis
– Adaptive Immunity
– Innate Immunity
– Inflammation
12. • How Does Immune Specificity Fit With Non-Specific
Cytokines
• Answer 1: Thru Receptors
– Receptors Expressed On Antigen Activated Cells
• Answer 2: Close Proximity To Cytokine Secreting Cells.
– Ex. APC-TH
– Cytokine Concentrations (TH) Are High Locally
– Only Interacting APC Gets Activated
• Answer 3: Short Half Life
– Short ½ Life Ensures Local Activity
Cytokines Are Non-Specific
22. Cytokine Receptors
• Multimeric receptors
• Common signal-transducing subunits
• Unique high affinity subunits
• High affinity subunits associated with
activation of target cell
37. • IL-1α, IL-1β, IL-1Ra, IL-18, IL-33
• DC, monocytes and macrophages
• IL-33: constitutively in smooth muscle &
bronchial epithelia
– Expression induced by IL-1 and TNF- in lung and
skin fibroblasts
– induce TH2 cytokines that promote T-lymphocyte
interactions with B cells, mast cells, & eosinophils
38.
39.
40.
41. Hematopoietin (Class I) Family
Cytokines
• small, soluble cytokines - communicate
between & among cells of the immune system
• some of the earliest members of this family
have hematopoietic functions, not all
• Defined on the basis of structural similarities
• defining structural feature: a four-helix bundle
motif, organized into four anti-parallel helices
42. Short helices of 8 to 10
residues:
IL-2, IL-4, & IL-3
Long-chain cytokines 10
to 20 Residues:
IL-6 and IL-12
43. • IL-2: signal the onset of T- & B-cell proliferation
• IL-6: signal the onset of B-cell differentiation to
plasma cells & antibody secretion
• Signal the differentiation of a T helper cell along
one particular differentiation pathway versus
another (e.g., IL-4 vs. IL-12)
• Initiate the differentiation of particular leukocyte
lineages (e.g., GM-CSF, G-CSF).
47. • Restriction of high-affinity IL-2 receptor to
only activated T cells – ensures proliferation of
antigen-activated CD4 and CD8 T cells when
physiological levels of IL-2 is present
• Congenital X-linked severe combined
immunodeficiency (XSCID) results from a
defect in the γ-chain gene - X chromosome
• deficiencies in both T-cell and NK cells
50. The gp130 Receptor Subfamily
• Targeted disruption of gp130 in mice during
embryonic development is lethal
• IL-6 & IL-12
• IL-6: important in the initiation of the immune
response
• IL-12 - critical for signaling differentiation of
helper T cells along the TH1 pathway
51. The Interferon (Class II) Cytokine
Family
• First to Be Discovered
• Type I interferons:
– IFN α : a family of about 20 related proteins, and
– IFN β – secreted by activated macrophages and
DCs & virus-infected cells
• Both are also produced by virally infected cells
after recognition of viral components by
pattern recognition receptors (PRRs)
52. Type II interferon
• IFN-γ : produced by activated T and NK cells
and released as a dimer
• Powerful modulator of adaptive IRs
– biasing T cell help toward the TH1 type
– inducing the activation of macrophages
– destruction of any intracellular pathogens
– differentiation of CTLs
• All three IFNs – increase MHC – enhance Ag
presentation
53. IFN family
• IL-10 – monocytes, T, B, and DCs
• Type III IFN family:interferon-λ:
– interferon- λ1(IL-29), interferon- λ 2 (IL-28A), and
interferon- λ 3 (IL-28B)
– up-regulate the expression of genes controlling
viral replication & host cell proliferation
54.
55. TNF Cytokine Family
• Signal Development, Activation, or Death
• Regulates the development, effector function,
and homeostasis of cells participating in the
skeletal, neuronal, and immune systems
• Cytokines of TNF Family – Soluble or
Membrane Bound
• Lymphotoxin-β, a membrane-bound cytokine
56. • TNF-α & TNF-β - Lymphotoxin-α or LT-α
• TNF-α: proinflammatory cytokine - during
infection: activated macrophages &
lymphocytes, fibroblasts, keratinocytes (skin
cells) produce
• Lymphotoxin- activated lymphocytes
• On binding to neutrophils, endothelial cells,
and osteoclasts (bone cells) -delivers
activation signals
• in other cells - increased expression of MHC
glycoproteins & of adhesion molecules.
57. • Lymphotoxin-β- a membrane bound cytokine
• BAFF and APRIL (B cell-activating factor/a
proliferation-inducing ligand) – B cell devt. &
homeostasis
• CD40L – cytokine expressed on surface of T cells
– B cell differentiation
• FasL or CD95L – induces apoptosis on binding to
Fas or CD95
• membrane-bound or in soluble form -
activeTNF family cytokines - assemble into
trimers – most homotrimer, some heterotrimer
58. Fas, FADD and
Procaspase-8:
Death inducing
signalling
complex (DISC)
Fas: FS-7-associated surface
antigen.
Fas ligand or FasL:
a homotrimeric type II
transmembrane protein that
belongs to the TNF family
59. RIP1 - Rest in
peace 1 (a
serine/threonine
kinase)
cIAP1 & cIAP2 –
ubiquitin ligases
62. SEFIR – similar expression to
fibroblast growth factor IL-17
receptor
ACT1 – adapter protein
Erk1 – extracellular signal
regulated kinase
C/EBPs – transcription factors
63. Chemokines - Direct the Migration
of Leukocytes Through the Body
• Relatively low in molecular weight (7.5-12.5kDa)
& structurally homologous
• Chemokine Receptors
• signal via interactions with a polymeric
GTP/GDP-binding “G protein.” This class of G-
Protein - Coupled Receptors (GPCRs)
65. Gα-GTP & Gβγ dimer
Signalling limited by
intrinsic GTPase activity of
Gα
Can be increased by
GTPase Activating Proteins
(GAPs) or RGSs –
Regulators of G-protein
signaling
Ras pathway – upregulate
integrin adhesion molecules
on the cell membrane
Rho – (3) – actin
polymerization and
promote cell migration
66. Cytokine-related diseases
• Bacterial septic shock
– Blood pressure drops, clots form, hypoglycemia ensues,
patient dies
– LPS triggers results in TNF release
– TNF induces IL-1 which induces IL-6 and IL-8
• Bacterial toxic shock and related diseases
– Superantigens trigger large numbers of T cells which
release massive amounts of cytokines (Super antigens are bacterial
toxins that bridge CD4 T cell receptors and the MHC class II molecules on APC’s,
bypassing the need for antigen)
• Lymphoid and myeloid cancers
– Some cancer cells secrete cytokines
• Chagas’ disease
– Trypanosoma cruzi infection results in sever immune
suppression - Depression of IL-2 receptor production
