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)