CYTOKINES AND RECEPTORS DR SANJITA DAS

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 K d receptors ( M) Cytokines regulate immune responses

Cytokines can activate many cells Ex. Cytokines secreted by T H 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 Cytokines

Innate and adaptive Immunity

Cytokine actions may be local and systemic Autocrine action Endocrine action circulation act at a distance from the site of infection Paracrine action act on a nearby cell act on cytokine-producing cell itself

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 T H 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

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-T H –Cytokine Concentrations (T H ) Are High Locally –Only Interacting APC Gets Activated Answer 3: Short Half Life –Short ½ Life Ensures Local Activity Cytokines Are Non-Specific

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)

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 Receptor Signalling (IFN  R)

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 Cytokine Antagonists

Macrophage Microbes Activation Dendritic cell Antigen presentation CD40 CD40LNaïve CD4+ T cell IL-12 T H 1 cell NK cell IFN-  Macrophage activation; killing of phagocytosed microbes CD8+ T cell Killing of infected cell Increased cytolytic activity NK cell

Roles of cytokines in innate immunity and inflammation Hours after LPS injection

CD4 + T H Cells Secret A Variety Of Cytokines Evidence For 2 Subsets –TH1–TH1 –TH2–TH2 Distinction Is Based On Cytokine Secretion Cytokine Environment Determines Which Subset Will Develop –IFN  for T H 1 (IL-12 and IL-18 from M ,DCs) –IL-4 for T H 2 T H 1 vs T H 2

T-bet Expression Results In T H 1 T-bet Suppresses T H 2 GATA-3 Results In T H 2 GATA-3 Suppresses T H 1 IFN-  Regulates Expression of T-bet (Stat 1) IL-4 Regulates Expression of GATA-3 (Stat 6) Transcription Factors T H 1 And T H 2

Active recruitment of the cells to the sites of infection  recognition of microbes  phagocytosis  destruction

TNF Low quantities (plasma conc.<10 -9 M) Moderate quantitie s High quantities (plasma conc.  M) Local inflammation Systemic effects Septic shock Leukocyte Activation Adhesion molecule Endothelial cell IL-1, chemokines Fever Low output Hypoglycemia Thrombus