Mucosal Immunity Reading

1
Mucosal Immunity Reading
May 9, 2005

• 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. 14275-300,
  1996
• Wright, JR. Immunoregulatory Functions of
  Surfactant Proteins. Nature Review Immunol.
  558-68, 2005.
• Cheroutre, H. Start at the beginning new
  perspectives on the biology of mucosal T cells.
  Annu. Rev. Immunol. 22217-46, 2004.
• Weiner, H. Oral tolerance immune mechanism and
  the generation of Th3-type TGF-beta-secreting
  regulatory cells. Microbes Infection 3947-954,
  2001.

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Lymphoid System

• Mucosal surface
• Exposed to the environment
• Challenge to protect
• We 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)

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Organization of Epithelial Layers

• Extrinsic barrier functions
• Exclude Antigens
• Tight junctions gt900 Da Air or fluid flow
  (mucus/Glycocalyx)
• Secrete factors
• Discourage bacterial colonization
• Antimicrobial function

Annu. Rev. Immunol. 14275-300, 1996
4
Respiratory Mucosal Surface
Wright, Jo Rae, Nature Reviews Immunol 558-68,
2005
5
SP-A D is Positioned to Interact with the
Environment
SP-A D
Tubular Myelin lattice network formed by
surfactant phospholipids
JCI 109707-712, 2002
6
Ability of the SPs to Protect Mucosal Surfaces in
Vivo
Group B Streptococcus
H. influenza
JI 165 3934-3940, 2000
7
Defensins

• Highly conserved
• Plants, insects vertebrates
• Amphiphilic molecules
• Dominated by one structure
• a-helical, b-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

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Distribution of Igs
Fundamental Immunology (5th Edition) Lippincott,
Williams Wilkins Chapter 31 (p.971)
9
Polymeric IgR (pIgR)
Nature Immunol. 21004-1009, 2001
10
Transcellular Transport
Fundamental Immunology (5th Edition) Lippincott,
Williams Wilkins Chapter 31 (p.975)
11
J-chain is Important for Binding SC and Mucosal
Transport of pIgA
JI 157750-754, 1996
12
Antigen presentation at Mucosal Surfaces
Inductive Sites Effector Sites
Annu. Rev. Immunol.14275-300, 1996
13
A Real M Cell
Nature Immunol. 21004-1009, 2001
14
Function of M Cells
Nature Immunol. 21004-1009, 2001
15
Epithelial Cells Produce Chemokines in Response
to Bacteria
Am J Physiol Gastrointest Liver Physiol
280G71217-26, 2001
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Are Immature DC Recruited to Mucosal Surfaces
CCL20 (MIP-3a)
Apical
Basolateral
Immature DC CCR1, CCR2 CCR5,CCR6
Am J Physiol Gastrointest Liver Physiol
280G1217-26, 2001
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G-Protein Signaling
18
G-Protein Signaling - Cont.
19
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

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Mucosal Memory T Cells Migrate with a Different
Homing Receptor
Mucosal
a4b7 integrin
Peripheral lymph nodes
CCR9 (TECK) Chemokine receptor
Chemokine CCL25
Lymphatic system
HEV
MAdCAM-1
ICAM-1
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Skin Memory T Cells Migrate with a Different
Homing Receptor
Blood
Peripheral lymph nodes
Skin
Intestine
CD162 (PSGL-1)selectin
Lymphatic system
CCR4 CCR10 chemokine receptors
Skin
Chemokines CCL17 / TARC CCL27 / CTACK
HEV
P-selectin
ICAM-1
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Epithelial Cells Selectively Produce Chemokines
J. Exp. Med. 4761-8, 2000
23
Activated T cells are Recruited to Certain
Lymphoid Tissues by Selective Expression of
Chemokines
JEM 195135, 2002
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Oral Tolerance
25
Two Mechanisms of Inducing Oral Tolerance
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Characteristics of IEL
Type A (ab) Type B (ab or gd) 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
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gd T cells

• gd T cells do not recognize Agic peptides like
  Antibodies abTCR
• TCR1015 Ab1011 Ags by rearranging V, D
  J ie junctional diversity
• They bind to limited Ags due to uneven length of
  g d chains.
• Infection model finds that Ag recognition is
  germline encoded and not due to diversity.
• gd TCR chains are determined by anatomic location
• Mouse spleen Vg1 Vg4
• Mouse intesting Vg7
• Non-classical MHC molecules
• T10 T22
• Shows CDR3g loop binds the T22 and not
  combination of peptideMHC like abCRs

CDR3g loop
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Immune EffectorsKathleen Kelly
kkelly_at_mednet.ucla.edu6-5562

• Reading
• Immunobiology (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. 23147-161, 2003.
• Mak, TM Lohoff. Roles of Interferon Regulatory
  Factors in T-helper-cell Differentiation. Nature
  Reviews Immunol. 5125-135, 2005.
• Russell, JH Ley, TJ. Lymphocyte-mediated
  cytotoxicity. Annu. Rev. Immunol. 323-370, 2002.