Cell:Cell Communication
Cells can communicate by:Soluble factorsSurface interactions
CytokinesSoluble factors that bind specific receptorsInfluence gene expression
May have pleiotropic or antagonistic effects
Autocrine: self-stimulating
Paracrine: stimulate adjacent cellsEndocrine: interact with cells far away, usually via circulation
Provide differentiation signalsProvide recruitment signalsProvide activation signals
Involved in T and B cell collaboration
Cytokines were originally discovered in the 1960’s
Were assessed in biologic assays
Originally Named based on their biologic effects
Noted in allogeneic mixed culture supernatants
Interleukins- cytokines from leukocytesNow named by numberIL-1….IL-30
Function of CytokinesLymphocyte activation
IL-1Produced by macrophages, Dendritic cells, B cells
Endogenous pyrogen
Functions on T and B cells
Promotes differentiation and clonal expansion
Increased expression of adhesion molecules on EC
IL-2
Secreted by Th1 cells
Causes proliferation/growth of activated T cells NK cells
Can be Autocrine
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Macrophage Activation
IL-4Secreted by Th2 cells Increases phagocytic activity Increases MHC II expression
IL-10
Secreted by TH2 cells Suppresses cytokine production Down-regulates MHC II expresssion
TH1 Vs TH2 CellsTH1
Inflammatory cell Activates macrophages Stimulates T cell responses
Secrete:IL-2IFN- inhibits TH2 proliferationTNF- activates macrophages
TH2
Helper T cell Stimulates Ab production
Secrete:IL-4 antagonizes IFN-IL-10 inhibits IFN- synthesisIL-5 stimulates B cell, eosinophil growth and differentiation
Disease States Associated with TH1/TH2 Responses
Autoimmune DiseasesExperimental allergic encephalomyelitis (EA) Inappropriate TH1 response to myelin basic protein inCNS
Leprosey Dominant, inappropriate TH2 response
Allergies TH2 responses, preferential production of IgE
AIDS TH1 to TH2 switch associated with disease progression
Inflammatory Cytokines
TNF- Increases vascular permeability- heat, swelling, accumulation of Ig and complement Induces expression of adhesion molecules Recruits cells to sites of inflammation Facilitates extravasation
Harmful if produced systemically (during sepsis) Increased vasopermeability causes loss of plasma volume, shock Triggers disseminated intravascular coaggulation, kidney, liver heart failure
IL-8 Causes inflammation, cell migration Alters conformation of adhesion molecules on monocytes, increases affinity for ICAM-1 encourages migration through tissues
Chemokines
Small peptides released by many cell types In response to injury As part of normal cell function (stromal elements)
Cells migrate towards increasing concentration (gradient) of chemokine Must have specific receptor for chemokine
Classified based on position of 2 of 4 conserved cysteins C-C chemokines have consecutive cysteins
MCAF (macrophage chemotactic/activating factor RANTES (made by activated T cells, attracts memory T cells MIP-1 (attract T cells)
C-X-C chemokines have another amino acid between cysteinsIL-8
SDF-1 (stromal-derived factor)
Several chemokines block secondary receptors for HIV SDF-1, RANTES, MIP-1 and
Interferons
Natural protective cytokines (innate)
IFN- produced by leukocytes in response to viral infectionIFN- produced by fibroblasts and other cell types in response to viral infection
Double stranded RNA causes expression of IFN
Causes activation of endoribonucleaseCleaves viral RNAInduces expression of proteins that inhibit translationCell killed, virus replication halted
IFN- produced by activated T cells, NK cellsIncreases expression of MHC I and IIInhibits virus replicationTH1 cytokine
Differentiation of Hematopoietic Cells
Effects on bone marrow progenitors
Erythropoietin: induces development of red blood cells
M-CSF: induces formation of macrophage colonies
G-CSF: induces formation of granulocyte colonies
GM-CSF: induces formation of granulocyte and macrophage colonies
IL-3: induces proliferation, differentiation of granulocytes and macrophages
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SDF-1
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Common -chain Receptor
Shared by receptors for IL-2,-4,-7,-9,-15,-21
Mutation in this gene causes inability to respond to any of these cytokines
Results in x-linked severe combined immunodeficiency
Cannot make B cells, T cells or NK cells
This disease has been “cured” in some patients by stem cell gene therapy
A second type of SCID defect can be caused by mutations in the IL-7 receptor
These patients have B and NK cells, no T cells
In humans, IL-7 is absolutely required for T cell development
Surface InteractionsFunction in adhesion and differentiation
Surface interactions can influence adhesion Increase expression of adhesion molecules alter conformation, allow greater adhesion
Extracellular matrix can trap cytokines concentrates and maintains them
Glycoaminoglycans bind chemokines helps recruit cells
Surface interactions induce differentiaionIn thymus: Binding MHC I leads to CD8 commitment
Binding MHC II leads to CD4 commitmentStrong binding of TCR with MHC leads to clonal deletion of developing cells
Nueroendocrine InteractionsStress may correlate with susceptibility to disease
Lymphocytes make about 20 neuroendocrine peptides
Related cytokines and receptors found in the brain
Hypothalamic-Pituitary-Adrenal axis (HPA)Hypothalamus: releases corticotropin-releasing hormone causes release of ACTH from pituitaryACTH acts on adrenal gland, produces glucocorticoids altered metabolism suppressed immune system feeds back on pituitary
Neuropeptides influence lymphocyte migration
Can alter chemokine receptor levels
Influence cytokine production
Alter function of thymic stromal elements
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Stress and HIV-1 disease progression:
High-stress individuals have faster disease progression
Stress hormone norepinephrine:
Increases HIV expression
Increases levels of CXCR4 (HIV co-receptor)
High-stress individuals respond poorly to therapy
Circulation/Extravasation
Granulocytes and monocytes travel exclusively in blood
Lymphocytes circulate in blood and lymph
Distribution of lymphocytes to tissues is not random
It is controlled by specific receptors on lymphocytes and on target tissues
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Virgin lymphocytes from blood entering into lymph node/spleen
Bind molecules on post-capillary venules
Squeeze between cells
Now in lymph
Circulation of Activated T Cells From Blood
1. If cells find site of infection:Endothelial cells of capillary are altered, and now express adhesion moleculesT cells bind these molecules, squeeze between endothelial cells
When Ag is removed, T cells become memory cells
Get swept into lymphatics, float to nearest lymph node
2. If cells do not find site of infection:
Become de-activated, convert to memory phenotype
Float to blood vessels in the skinBind to adhesion molecules on post-capillary venules in skin
Squeeze between endothelial cells, are swept away into lymph
This distributes memory cells throughout the body
Summary of T Cell Movement
Naïve T cells: Exit blood at post-capillary venules in nodes
Activated T cells in blood :
If find area of infection Bind to adhesion molecules on EC Extravasate Swept to local node after become memory cells
If do not find area of infection Become de-activated memory cells Exit blood at post-capillary venules in skin Drift to nodes near that site
Trafficking is controlled by: Appearance/disappearance of adhesion molecules on endothelial cells Appearance/disappearance of their ligands on lymphocytes
At the site of inflammation, pro-adhesion molecules induced on ECLigands on WBCs bind, cell slows down and rolls (marginalization)This induces expression of true adhesion molecules on WBC (also EC)
Additional signalsInduce cells to moveTowards the site of inflammation
Cell extravasates
TABLE I. Examples of Some Adressins and Selectins
EC Receptor: Expressed: Affinity: Receptor:(Addressin) (Selectin)
ELAM-1 Early Low Various CHO
VCAM-1 Medium Moderate-Hi VLA-4 (a4b1)LPAM-1(a4b7)
ICAM-1, 2 Late High LFA-1 (a1b2)MAC-1 (amb2)p150/95 (a2b2)