CYTOKINES AND RECEPTORS

Chapter 12
 What Is A Cytokine?

• Low molecular weight proteins (30 KDa)

• Bind receptors, alter gene expression
• Can bind the secreting cell (autocrine)
• Can bind another cell close by (paracrine)
• Few cases bind another cell far away (endocrine)
• Very low Kd receptors (10-10-10-12 M)
• Cytokines regulate immune responses
 Cytokines

• Cytokines can activate many cells

• Ex. Cytokines secreted by TH can affect B-
cells, CTLs, M, NK
• A cytokine can be pleiotropic (different
effect on different cells)
• Synergism, redundancy, antagonism
• Interleukins, monokines, lymphokines,
chemokines, term CYTOKINE includes all
of them
 Cytokine Categories

• 4 Categories
– TNF family
– Chemokine family
– Interferon family
– Hematopoietin family
• Hematopoietin family
 -helical structure prevalence
– Little or no -sheet
– Ex. IL-2 and IL-4
– Amino acid sequences vary considerably
 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
• See Appendix For Complete List And Function
• Activities Established Thru Recombinant Cytokines
(Simplistic Approach), In Vivo Function Can Vary
 Cytokines Are Non-Specific
• 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
 Cytokine Receptors
• 5 Major Families
– Immunoglobulin Superfamily
– Hematopoietin Receptor Family (Class I)
– Interferon Receptor Family (Class II)
– TNF Receptor Family
– Chemokine Receptor Family
• Class I and II (Majority Of Receptors)
– Multimeric
– Upon Receptor Engagement, Tyrosine
Phosphorylation
Hematopoietin Receptor Family (Class I)
 Receptor Signalling (IFNR)
• Ligand Binds  Subunit
• Ligand Binding Causes Dimerization of Receptor
• JAKs Get Activated
– Phosphorylation of tyrosine residues on receptor
– Phosphorylation of JAKs themselves
• STATS Dock Receptor
– Phosphorylation of STATs by JAKs
• Dimerized STATs Translocate To Nucleus
• Gene Expression
 Cytokine Antagonists
• Antagonists Exist In 2 Forms
– Receptor Antagonists (Bind Receptor, No Activation)
– Bind Cytokine (Prevent Cytokine From Binding Receptor)
• Well Studied Example: IL1Ra
• In Many Cases Antagonist Is A Soluble Receptor
– Derived From Proteolytic Cleavage Of Extracellular Domain Of
Particular Receptor
– IL-2, IL-4, IFN, IFN
• Viruses Produce Cytokine Mimics Or Cytokine Binding
Proteins
– Ex. Poxviruses Produce IL-1-Binding Protein And TNF-binding-
protein
– These Agents Offer Viruses An Advantage
 TH1 vs TH2

• CD4+ TH Cells Secret A Variety Of Cytokines

• Evidence For 2 Subsets
– TH1
– TH2
• Distinction Is Based On Cytokine Secretion
• Cytokine Environment Determines Which Subset
Will Develop
– IFN for TH1 (IL-12 and IL-18 from M,DCs)
– IL-4 for TH2
 Transcription Factors
TH1 And TH2
• T-bet Expression Results In TH1
• T-bet Suppresses TH2
• GATA-3 Results In TH2
• GATA-3 Suppresses TH1
• IFN- Regulates Expression of T-bet (Stat 1)
• IL-4 Regulates Expression of GATA-3 (Stat 6)