Initiation of the immune response

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Initiation of the immune response

• March 21, 2008
• Penny Morel 4-0343
• morel_at_pitt.edu

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Outline

• Immune system at rest
• Role of antigen
• Dendritic cells
• Consequence of DC/T cell interaction
• IL-2 and its receptor

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Players in the immune response

• Dendritic cells located in tissues, high
  endocytic capacity, sample the environment for
  antigens, express low levels of MHC, CD80, CD86,
  express CCR1, CCR6
• Naïve T cells in T cell area of LN,
  recirculating, express CD62L, CD45RO, CCR7, CXCR4
• Naïve B cells in follicles of LN, recirculating,
  contact antigen as leave HEV, express IgM, CD62L,
  CCR7, CXCR5
• Antigen immunogenicity, route, dose, adjuvant
• Lymph node structure and trafficking

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T and B cells localize to different areas in
spleen and lymph node B cells follicles T
cells peri-arterial, between follicles They
enter the lymphoid tissues via the HEV - high
endothelial venules
Science 286 2058, 1999
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Organization is controlled by chemokines Staining
for CXCL13 (BLC) in B cell area and
CCL21/CCL19 (SLC/ELC) in T cell area.
Science 286 2058, 1999
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Curr. Opin. Immunol. 13 670, 2001
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Adhesion molecules important in trafficking

• Selectins bind to addressins on endothelium -
  initiate rolling. e.g. L-selectin (CD62L) binds
  to glyCAM-1 on the HEV
• Integrins - stimulate firm adhesion. LFA-1 binds
  to ICAM-1
• Different tissues express different addressins

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Neutrophil rolling in post-capillary venules in
vivo
ROLLVIVO.MOV_better_invivo
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Neutrophil firm adhesion
FIRM_ADH_VIVO.MOV
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Neutrophil emigration in vivo
EMIGRATI.MOV
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ANTIGEN plays an important role in initiating
immune response A Localization and Dose
A Indifference/ignorance. Antigen is in the
periphery and never comes to LN B Immune
response Antigen traffics to LN and encounters
naïve T and B cells C Exhaustion High dose of
widespread antigen - deletes T cells D
Peripheral persistence potent response is
induced but virus hides out in the periphery, go
latent and persist Immunological reviews
156199, Zinkernagel et al, 1997
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Immunological reviews 156199, Zinkernagel et al,
1997
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Figure A-2
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Structure and physiology of the responding lymph
node
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Large molecular weight molecules are excluded
from LN cortex LPS is also excluded.
Dextran MHC class II stain LPS
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Protein antigens (OVA, HEL) travel though fiber
conduits to space around HEV
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DC subsets in the LN
Nature Immuno. 4733
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Features of immature and mature DC
Banchereau and Steinman. Nature 392245, 1998
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DC respond to pathogens and tissue damage
Nature 425460, 2003
PAMP DAMP P pathogen D damage
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Two waves of Ag into LN 1) Soluble
via conduits 2) DC-associated
B220 stains B cells EaRFP is the antigen that was
injected in the skin Y-Ae stains the MHC-peptide
complex derived from the antigen Immunity1947,
2003
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Nature Immunol. 4733, 2003
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Activation of T cells

• Induces IL-2 production
• Induces IL-2R expression
• Induces anti-apoptotic gene - Bcl-XL
• Enhances cell adhesion
• Proliferation - as a result of autocrine response
  to IL-2
• Differentiation into effector cells

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DC/T cell interaction results in clonal expansion
of T cells
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Interleukin-2 and its receptor

• High affinity IL-2R consists of three chains
  ???????
• Resting T cells express ??and ? chains of IL-2R
• Activation induces expression of IL-2R ? chain
  (CD25)
• Activation of naïve T cells induces expression
  of IL-2.
• IL-2 is a T cell growth factor
• IL-2 also has important functions on NK and B
  cells

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Expansion of T cells requires signal 3- can be
IL-2
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Science 280243. 1998