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Cell:Cell Communication
Cells can communicate by:
Soluble factors
Surface interactions
Cytokines
Soluble factors that bind specific receptors
Influence gene expression
May have pleiotropic or antagonistic effects
Autocrine: self-stimulating
Paracrine: stimulate adjacent cells
Endocrine: interact with cells far away, usually via circulation
Provide differentiation signals
Provide recruitment signals
Provide activation signals
Involved in T and B cell collaboration
Cytokines were originally discovered in the 1960’s
Noted in allogeneic mixed culture supernatants
Were assessed in biologic assays
Originally Named based on their biologic effects
Interleukins- cytokines from leukocytes
Now named by number
IL-1….IL-30
Function of Cytokines
Lymphocyte activation
IL-1
Produced 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-4
Secreted by Th2 cells
Increases phagocytic activity
Increases MHC II expression
IL-10
Secreted by TH2 cells
Suppresses cytokine production
Down-regulates MHC II expresssion
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TH1 Vs TH2 Cells
TH1
Inflammatory cell
Activates macrophages
Stimulates T cell responses
Secrete:
IL-2
IFN-g inhibits TH2 proliferation
TNF-b activates macrophages
TH2
Helper T cell
Stimulates Ab production
Secrete:
IL-4 antagonizes IFN-g
IL-10 inhibits IFN-g synthesis
IL-5 stimulates B cell, eosinophil growth
and differentiation
Disease States Associated with TH1/TH2 Responses
Autoimmune Diseases
Experimental 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,b (attract T cells)
C-X-C chemokines have another amino acid between cysteins
IL-8
SDF-1 (stromal-derived factor)
Several chemokines block secondary receptors for HIV
SDF-1, RANTES, MIP-1  and b
Interferons
Natural protective cytokines (innate)
IFN- produced by leukocytes in response to viral infection
IFN-b produced by fibroblasts and other cell types in response to viral infection
Double stranded RNA causes expression of IFN
Causes activation of endoribonuclease
Cleaves viral RNA
Induces expression of proteins that inhibit translation
Cell killed, virus replication halted
IFN-g produced by activated T cells, NK cells
Increases expression of MHC I and II
Inhibits virus replication
TH1 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 g-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 Interactions
Function 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 differentiaion
In thymus:
Binding MHC I leads to CD8 commitment
Binding MHC II leads to CD4 commitment
Strong binding of TCR with MHC
leads to clonal deletion of developing cells
Nueroendocrine Interactions
Stress 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 pituitary
ACTH 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
Stress hormone norepinephrine:
Increases HIV expression
Proportion AIDS-free
MedianCD4lv(%ymphocts)
High-stress individuals have faster disease progression
(% lymphocytes)
CD4 T cell level
Stress and HIV-1 disease
progression:
5
0
Increases levels of CXCR4 (HIV co-receptor)
3
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2
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Proportion alive
High-stress individuals respond poorly to therapy
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Years since MACS entry
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 molecules
T 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 skin
Bind 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 EC
Ligands on WBCs bind, cell slows down and rolls (marginalization)
This induces expression of true adhesion molecules on WBC (also EC)
Cell extravasates
Additional signals
Induce cells to move
Towards the site of
inflammation
TABLE I. Exa mples of Some Adressins and Selectins
EC Receptor:
(Addressin)
ELAM-1
VCAM-1
Expre ssed:
Affinit y:
Early
Medium
Low
Moderate-Hi
ICAM-1, 2
Late
High
Receptor:
(Selectin)
Various CHO
VLA-4 (a4b1)
LPAM-1(a 4b7)
LFA-1 (a1b2)
MAC-1 (amb2)
p150/95 (a2b2)