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    • B/T cell interaction March 27, 2009 Penny Morel 4-0343, morel@pitt.edu
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    • B cell activation requires:
      • Antigen binding to Ig on cell surface
      • CD40/CD40L interaction with activated T cell
      • Cytokines produced by activated T cells: IL-4, IL-5, IFN- 
      • B cell activation leads to: proliferation and differentiation into antibody-producing cells (plasma cells)
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    • Science 281:96, 1998 T and B cells interact in the T cell areas of the LN, activated B cells form a germinal center
    • Spec. T cells blue B cells brown T cells brown Spec. B cells blue Spec T cell brown Spec B cell blue OVA-HEL conjugate OVA + HEL
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    • Germinal Center Reaction
      • Initial contact between B and T cells occurs at the edge of the follicle
      • Activated T and B cells migrate into the follicle - initiate germinal center. Only T and B cells recognizing the same antigen are present in GC - clonal populations. Specialized Tfh (follicular helper) subset
      • GC develop around a network of follicular dendritic cells (FDC)
      • Role of GC: generate memory B cells and potentiate differentiation into high affinity antibody-producing B cells
    • Immunity 30, March 20, 2009, Fazilleau et al
    • Annual Reviews
    • Immunity 29, 2008, Pages 7-9
    • Nature Immunology 10, 371 - 372 (2009)
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    • Figure 9-7
    • Figure 9-19
    • Trends Immunol. 23:31, 2002
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    • (f) Semiquantitative RT-PCR analysis of the expression of AID and IgG1 post-switch transcripts by eGFP+, eGFP+huCD2+ or eGFP-huCD2-CD4+ B cell–T cell conjugates from the draining popliteal lymph nodes of 4get-KN2 mice, sorted 14 d after L. major infection, normalized to Pax5 expression. Results are representative of at least two independent experiments with three serial dilutions (wedges). (g) Section of a draining popliteal lymph node from a KNZ–IFN-gamma reporter mouse 14 d after L. major infection, stained for huCD2 (IL-4 secretion), eYFP (IFN-gamma competence) and PNA (GCs). Original magnification, times 200. Image is representative of at least two independent experiments with six lymph nodes. (h) Semiquantitative RT-PCR analysis of the expression of IgG1 and IgG2a post-switch and germline transcripts and AID by huCD2+CD4+CD19+ (CD2+) or eYFP+ B cell–T cell conjugates (doublets) or eGFP-huCD2-CD4- CD19+ singlets from the draining popliteal lymph nodes of KN2–IFN-gamma mice, sorted 14 d after L. major infection, normalized to Pax5 expression. Results are representative of at least two independent experiments with three serial dilutions .
    • Immunity 30, March 20, 2009, Fazilleau et al
    • Other cytokine effects on B cells
      • IL-2: stimulates proliferation
      • IFN-  : Inhibits proliferation Downregulates MHC expression
      • IL-4: Stimulates proliferation upregulates MHC expression
      • IL-10: Stimulates proliferation upregulates MHC expression induces B cell differentiation
      • IL-13: similar effect to IL-4 on human B cells no effect on mouse B cells
    • Other cytokine effects on B cells
      • TGF-  : inhibits proliferation
      • IL-17: induces germinal center formation Maintains GC may play a role in auto-antibody production
      • IL-6: Induces B cell proliferation induces B cell differentiation increase IgG production
    • Co-stimulatory molecules are required for GC formation: CD40/CD40L, CD28 and ICOS Members of the TNF family are also required
    • Immunol. Rev. 156:127, 1997
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    • B cells in the GC
      • Proliferate in dark zone - centroblasts
      • Undergo somatic hypermutation during this phase
      • Positive selection for high affinity - centrocyte:FDC interaction
      • Negative selection for autoreactive B cells - B:T cell interaction
    • CDR1, 2, 3 of Ab molecule contact antigen
    • Open square: early primary Closed square: late primary Diamond: secondary Triangle: tertiary Affinity of Ab increases with each immunization and so does the number of mutations Fundamental Immunology Textbook Editor W.E. Paul
    • Mutations are clustered in the CDRs and contribute to the increase in affinity. Fundamental Immunology Textbook Editor W.E. Paul
    • Location of cells in GC determined by chemokines CXCL13 in light zone attracts CXCR5 + T and B cells CXCL12 in dark zone attracts CXCR4 + B cells
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    • Figure 9-15
    • Trends Immunol. 22:361, 2001
    • Immunity 30, March 20, 2009, Fazilleau et al
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    • Figure 9-10
    •