Advanced Course in Basic & Clinical Immunology
February 20, 2018
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T-B collaboration
Shiv Pillai MD, PhDMassachusetts General Hospital
Harvard Medical School
SLOs - T and B cell zones
CCL19 and CCL21draw naïve T cells to T cell zones
CXCL 13 brings naive B cells to follicle
BAFF keeps B cells alive
Advanced Course in Basic & Clinical Immunology
February 20, 2018
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Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
Antigen Delivery to Follicular B cells
Multivalent Structures can be T-independent antigens
Advanced Course in Basic & Clinical Immunology
February 20, 2018
3
HAPTENS
T-independent ANTIGENS
T-dependent ANTIGENS
Haptens, Antigens, Immunogens
• Haptens are small molecules or moieties. They are antigens but not immunogens
• All immunogens are antigens
• All antigens are not immunogens
Advanced Course in Basic & Clinical Immunology
February 20, 2018
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Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
T-DEPENDENT ACTIVATION OF B CELLS
Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
T-B cell Migration and Interactions
Advanced Course in Basic & Clinical Immunology
February 20, 2018
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Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
B Cell Antigen Presentation to Helper T cells
Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
Distinct B and T cell epitopes must be linked
Advanced Course in Basic & Clinical Immunology
February 20, 2018
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Y
Y
MHCclass II
(loaded)
TCR
T
B
CD4
CD40
gp 39/CD40L
BCR
activated
The BCR internalizes specific protein antigens forprocessing and presentation to activated T cells
Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
Helper T cell Activation of B Cells (1)
Advanced Course in Basic & Clinical Immunology
February 20, 2018
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Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
Helper T cell Activation of B Cells (2)
Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
Events in T–Dependent Humoral Responses
Advanced Course in Basic & Clinical Immunology
February 20, 2018
8
Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
T Follicular Helper Cell Induction and Function
Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
Germinal Centers in Lymphoid Organs
Advanced Course in Basic & Clinical Immunology
February 20, 2018
9
Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
B Cell Antigen Presentation to Helper T cells
Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
Events in T–Dependent Humoral Responses
1
2
3
Advanced Course in Basic & Clinical Immunology
February 20, 2018
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Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
Sequential T-B interactions in immunity
1. T B - Forms extrafollicular B cell focus
2. B T - Generates T follicular helper cells
3. T B - Selection of high affinity B cells in light zone by TFH cells
Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
B Cell Selection in Germinal Centers
Advanced Course in Basic & Clinical Immunology
February 20, 2018
11
Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
Ig Heavy Chain Isotype Switching
, IgG4
Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
T cell subsets and human isotype switching (evolving)
TFH2 - IgE and IgG4 (cells make IL-4 andare BATF positive)
TH2 cells- GATA-3+; NOT drivers of classswitching
Advanced Course in Basic & Clinical Immunology
February 20, 2018
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Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
Heavy Chain Isotype Switching
Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
Heavy Chain Isotype Switching
Advanced Course in Basic & Clinical Immunology
February 20, 2018
13
Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
Somatic Mutations in Ig V genes
Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
An Overview of Affinity Maturation
Advanced Course in Basic & Clinical Immunology
February 20, 2018
14
Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
Activation Induced Cytidine Deaminase
Neuberger JEM, 2007
AID and Somatic Mutation
Advanced Course in Basic & Clinical Immunology
February 20, 2018
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Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
Molecular Mechanism of Ig Class Switching - I
Copyright © 2011 by Saunders, an imprint of Elsevier Inc.Abbas, Lichtman, and Pillai. Cellular and Molecular Immunology, 7th edition. Copyright © 2011 by Saunders, an imprint o
Molecular Mechanism of Ig Class Switching - II
Advanced Course in Basic & Clinical Immunology
February 20, 2018
16
Terminal differentiation into plasma cells
Signals: BCR, CD40, Cytokines such as IL-21 and IL-6
IRF4 and BLIMP-1 induce the XBP-1 transcription factor, ER stress
signals control splicing of XBP-1
BAFF family receptor BCMA for survival of long-lived plasma cells in
Bone marrow
IRF-4Blimp-1XBP-1
Pax-5
Mature B cell GC B cell Plasma cell
Bcl-6
Distinct transcription factors characterize mature B cells,GC B cells and plasma cells
Advanced Course in Basic & Clinical Immunology
February 20, 2018
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BCMA is critical for the maintenance of long-lived plasma cells
Shapiro-Shelef and Calame, NRI 5, 230-242
Helper T cell
T cell response
Initial T-B interaction
DC
Activated B cells generally REQUIRED for CD4+ T cell memory
CD4+ T memory cells
B-T interactions between previously activated cells
Advanced Course in Basic & Clinical Immunology
February 20, 2018
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An overview of B cell activation
Quietly into the night…….