Mucosal Immunity – Reading

Immunobiology (6th Edition) Janeway, Travers, Walpert and Capra Chapter 10 (p. 432-445).

Neutra, MR et al Antigen sampling across epithelial barriers and induction of mucosal immune responses. Annu. Rev. Immunol. 14:275-300, 1996

Wright, JR. Immunoregulatory Functions of Surfactant Proteins. Nature Review Immunol. 5:58-68, 2005.

Cheroutre, H. Start at the beginning: new perspectives on the biology of mucosal T cells. Annu. Rev. Immunol. 22:217-46, 2004.

Weiner, H. Oral tolerance: immune mechanism and the generation of Th3-type TGF-beta-secreting regulatory cells. Microbes & Infection 3:947-954, 2001.

May 9, 2005

Lymphoid System

= Mucosal surface Exposed to the environment

Challenge to protectWe have 5 mucosal surfaces

Nasopharyngeal Respiratory tract Oral Intestinal tract Urogenital tract

Specialized functions Acquiring or excreting Reproduction

Suppress Immune responses to food & commensal bacteria Gut (1014 organisms)

Organization of Epithelial Layers

Annu. Rev. Immunol. 14:275-300, 1996

Extrinsic barrier functions•Exclude Antigens

Tight junctions >900 Da Air or fluid flow (mucus/Glycocalyx)

•Secrete factors Discourage bacterial

colonizationAntimicrobial function

Respiratory Mucosal Surface

Wright, Jo Rae, Nature Reviews Immunol 5:58-68, 2005

SP-A & D is Positioned to Interact with the Environment

JCI 109:707-712, 2002

Tubular Myelin = lattice networkformed by surfactant phospholipids

SP-A & D

Ability of the SPs to Protect Mucosal Surfaces in Vivo

Group B Streptococcus

H. influenza

JI 165: 3934-3940, 2000

Defensins

Highly conserved Plants, insects & vertebrates

Amphiphilic molecules Dominated by one structure: -helical, -pleated sheet, proline-rich

Secreted by many cell types Innate immune cells (PMNs) Paneth cells/glands (intestinal crypts) Epithelial cells (GU & Respiratory tract & skin)

Function as Broad-spectrum microbicides Act against gram – ,gram + microorganisms,

fungi, mycobacterium, spirochetes and viruses Permeabilization of outer mb

Distribution of IgsLevels of immunoglobulins in human external secretions (g/ml)

Secretion IgA IgG IgM

Serum 1,500 10,047 1,500

Tears 80-400 Trace amounts-16

0-18

Nasal fluid 70-846 8-304 0

Whole saliva 194-206 42 64

Intestinal fluidb 166 4 8

Urine 0.1-1.0 0.06-0.56 d

Cervical fluid 3-133 1-285 5-118

Vaginal fluid 35 52 d

Fundamental Immunology (5th Edition)

Lippincott, Williams & Wilkins Chapter 31 (p.971)

Polymeric IgR (pIgR)

Nature Immunol.

2:1004-1009, 2001

Transcellular Transport

Fundamental Immunology (5th Edition)

Lippincott, Williams & Wilkins Chapter 31 (p.975)

J-chain is Important for Binding SC and Mucosal Transport of pIgA

JI 157:750-754, 1996

Antigen presentation at Mucosal Surfaces

Annu. Rev. Immunol.14:275-300, 1996

Inductive SitesEffector Sites

A Real M Cell

Nature Immunol. 2:1004-1009, 2001

Function of M Cells

Nature Immunol.

2:1004-1009, 2001

Epithelial Cells Produce Chemokines in Response to Bacteria

Am J Physiol Gastrointest

Liver Physiol 280:G71217-26, 2001

Are Immature DC Recruited to Mucosal Surfaces

Am J Physiol Gastrointest

Liver Physiol 280:G1217-26, 2001

Apical

Basolateral

Mature DCCCR7

Immature DCCCR1, CCR2CCR5,CCR6

CCL20(MIP-3)

G-Protein Signaling

G-Protein Signaling - Cont.

Naïve and Memory T Cells Travel in Different Paths

Naïve (have not seen their antigen) T cells travel in the blood and lymphatics

Memory T cells (have been activated by their antigen) can also travel through tissues

Mucosal Memory T Cells Migrate with a Different Homing Receptor

Peripherallymphnodes

Lymphaticsystem

MAdCAM-1

47: integrin

ChemokineCCL25

CCR9 (TECK):Chemokine receptor

Mucosal

HEV

ICAM-1

Skin Memory T Cells Migrate with a Different Homing Receptor

BloodPeripherallymphnodes

Lymphaticsystem

Intestine

SkinChemokinesCCL17 / TARCCCL27 / CTACK

CD162 (PSGL-1):selectin

CCR4 & CCR10: chemokine receptors

Skin

HEVP-selectinICAM-1

Epithelial Cells Selectively Produce Chemokines

J. Exp. Med. 4:761-8, 2000

Activated T cells are Recruited to Certain Lymphoid Tissues by Selective Expression of Chemokines

JEM 195:135, 2002

Oral Tolerance

Two Mechanisms of Inducing Oral Tolerance

Characteristics of IEL

Type A () Type B ( or )

Conventional MHC I & II Non-Conventional MHC

Memory response No memory response

Thymic dependent Mostly thymic independent

Negative & positive selection Only positive selection (autoimmune)

Both produce cytokines & chemokines

Inflammatory response Anti-inflammatory response

T cells

T cells do not recognize Ag’ic peptides like Antibodies & TCR

o ~ TCR:1015 & Ab:1011 Ags by rearranging “V”, “D” & “J” ie junctional diversity

They bind to limited Ags due to uneven length of & chains.

Infection model finds that Ag recognition is germline encoded and not due to diversity.

TCR chains are determined by anatomic location

● Mouse spleen: V1 & V4● Mouse intesting V7

Non-classical MHC molecules● T10 & T22

Shows CDR3loop binds the T22 and not combination of peptide:MHC like CRs

CDR3loop

Immune EffectorsKathleen Kelly kkelly@mednet.ucla.edu6-5562

ReadingImmunobiology (5th Edition) Janeway, Travers, Walpert and Capra

Chapter 10 (p. 381-402) and Chapter 8 (p. 295-340)

Agnello D, et al. Cytokines and transcription factors that regulate T helper cell differentiation: new players and new insights. J Clin Immunol. 23:147-161, 2003.

Mak, TM & Lohoff. Roles of Interferon Regulatory Factors in T-helper-cell Differentiation. Nature Reviews Immunol. 5:125-135, 2005.

Russell, JH & Ley, TJ. Lymphocyte-mediated cytotoxicity. Annu. Rev. Immunol. 323-370, 2002.