Summary
ADVANCED IMMUNOLOGY
Course 1 – cytokines
General
• Cytokines are the communication molecules of the immune system (messengers).
• The immune system is located at different sites in the body (primary and secondary lymphoid
tissues).
• The key to a successful immune system is the rapid and effective communication between
the imm syst cells.
• Mediators of the effector functions of the imm syst (protecting against invading organisms,
regulate intensity and duration of the response).
• Chemokines are cytokines that induce chemotaxis.
• Most cytokines are soluble proteins → released by one cell → bind to Rs on another cell →
biological effects (proliferation or enhancing survival, differentiation, cell death, migration –
pleiotropy (1 cytok and multiple effects), redundancy (more than one cytok and same eff),
synergy (two or more cytok work together), antagonism (one cytok inactivates the other)).
• BUT some are membrane-bound forms (TNF fam).
• Ligand-R interaction of very high affinity (very potent)!!!
• Endocrine; on distant cells (via the blood) – paracrine; on nearby cells – autocrine; on itself.
• Innate imm cytok; IL1, TNFα, CXCL8 (by neutros, macroph).
• Adaptive imm cytok; IL2, IL4, IL17 (by T and B lymphos).
, • Cytok can also act in cascades.
• The cells of the imm syst are subject to control by a network of cytok interactions.
• Specificity in the cytok system; naïve T cell with certain Rs, can be activated and then it
changes its Rs (some are upregulated others are downregulated), in this way you can have a
spec reaction with redundant cytok that act on diff cells. The cells need to be in the right
activation state by ag-activation.
• Specificity; cytok is very potent and only released where it is needed, act in a limited time
frame and over a short distance (half-life in the extracellular milieu is short).
• Table; each family is distinguished by the structure of ligand and R and the nature of the
signaling pathways induced.
IL1 Receptor signaling
• Immunoglobulin-like domains of the R, always 2 diff
chains.
• IL1 R is act when IL1 binds, TIR domains are active,
recruit kinase MyD88, recruit IRAKs and TRAF6, contains
ubiquitin ligase, puts the ub chains on cytoplasmic
components (TAB1 and 2 on TAK1), 2 diff signaling
pathways are turned on (MAPK (AP1) and NF-κB
pathway → cytok expression)
Hematopoietin (Class I) family cytokines
• Produced by many cells and have divergent activities
(differentiation, activation, ab secretion etc).
• Four-helix bundle motif organized in four antiparallel
helices.
• IL2, 4 and 3 have short helices, IL6 and IL12 long helices.
• The Rs have 2 types of prot domains; Ig- like domain of β sheets and domains with homology
to fibronectinIII (FN) domain (2 tandem FNIII domains from cytok-binding homology regions
(CHRs)) and they have multiple subunits.
[2]
,• Subfam of hematopoietin fam cytk Rs share common subunits; γ, β and gp130. Three
subclasses of Class I cytok are based on the common cytok R unit.
• Class I γ-chain (eg IL2R) bearing subfamily:
➢ IL2R exists in low, intermediate and high-affinity forms → marked by the presence of
accessory R chains & lymphocytes shift to expression of high-aff form during
activation events (low to high on CD4+, CD8+ and B cells – intermediate NK cells and
resting T cells).
• Class I β-chain bearing subfamily:
➢ Rs for IL3, IL5 and GM-CSF, each cytok binds to unique α subunit, the β subunit is a
shared signal-transducing prot.
➢ These cytok exhibit redundancy (activate granulocytes (eosinos and basophils),
stimulate leukocyte diff, activate monocytes).
➢ If IL3 and GM-CSF are present, the more abundant one has more chance to activate
the alfa chain with the beta chain, there is competition for the common subunit and
this produces antagonistic effects between Class I cytok.
➢ Activation of the IL3 R complex by IL3 → very complicated.
• Class I gp130 R subfamily:
➢ Includes IL6 Rs and targeted disruption is lethal in embryonic mice, ligand spec
dimers or trimers are expressed with the gp130 subunit.
➢ Signaling pathways induced are similar to those induced by IFN.
➢ IL6 classical and trans-signaling;
Classical = IL6 binds to IL6 R together with gp130 subunit, the 2 chains come
together, JAK is activated and STAT and others. This controls central homeostatic
processes and immunological outcomes, acute-phase response, glucose metabolism,
hematoepoiesis and regulation of the neuroendocrine system, hyperthermia, fatigue
and loss of appetite.
Trans-signaling = IL6 can also activate cells that only express one R chain (gp130),
soluble IL6R is present (chain be released from cell membrane by proteases), can
capture an IL6 molecule in the extracellular milieu and then bind to gp130 AGONIST.
But gp130 can also be released by the cell due to proteases, then you have a trimer
ligand that is formed (gp130, IL6 R and soluble IL6), this cannot signal anymore bec
there is no link to the intracellular part of the cell ANTAGONIST. This is involved in
colitis, tissue fibrosis, inflammatory arthritis, allergy, infection, neuroinflammation,
CV disease and inflamm induced cancers. Also important for the recruitment and
apoptosis of leukocytes, maintenance of the eff function of T cells and the inflamm
act of stromal tissues.
sIL6R is released by neutros, monocytes and act T cells, it can act as an alarmin that
promotes IL6 trans-sign within the local milieu as a potential danger response (when
released by neutros).
[3]
, Interferon (Class II) cytokine family
• Type I interferons
➢ 18-20 kDa dimers with antiviral effect, very !r in the defence against viruses.
➢ Secr by act macrophages and DC; IFNα (20 related prots) and IFNβ.
• Type II interferons
➢ IFNγ.
➢ Dimer produced by act T/NK cells.
• Type III interferons
➢ IFNλ.
• Receptors for IFN are heterodimers; FNIII domain
(conserved cysteine residues like Class I Rs) and the
fam has at least 12 chains, capable of binding to 27 or
more diff cytok.
• R signaling; through the JAK-STAT pathway
Cytok brings together the 2 R chains on the cell surface
(dimerization), this activates JAKs, they phosphorylate
the STATs, the P-STATs dimerize and translocate into
the nucleus and act as transcription factor (STAT can
activate spec genes that have the right transcription
element).
Inhibition of the pathway occurs via PIAS, SOCS and protein Tyr phosphatases.
Spec JAKs and STATs are used in the pathway for spec cytok responses → this is how it is
specified.
[4]
