Initiation of the immune response

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Initiation of the immune response

• March 19, 2007
• 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
• Change in trafficking patterns
• IL-2

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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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Lymphocyte trafficking at rest
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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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Figure A-4
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Dendritic cells and the control of immunity
Banchereau and Steinman Nature 392245
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DC subsets in the LN
Nature Immuno. 4733
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Immunology Cell Biol. 80463, 2002
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Nature Rev. Immunol. 2151, 2002
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Nature Rev. Immunol 5617, 2005
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Features of immature and mature DC
Banchereau and Steinman. Nature 392245, 1998
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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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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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Red antigen Blue B cells Green
conduits Red antigen Blue B cells Green
CD40 (DC)
30 minutes after injection
Nature Immunol. 4733, 2003
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If the site of antigen injection is removed
5hr after injection Cells proliferate Less
upregulation of CD25 No DTH response Immunity
1947, 2003 So migration of DC to LN
is necessary for sustained T cell activation and
effector T cells
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DC/T cell interaction results in clonal expansion
of T cells
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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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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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IL-2R signaling
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Expansion of T cells requires signal 3- can be
IL-2
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Science 280243. 1998
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