presentation
TRANSCRIPT
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)
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 blueB cells brown
T cells brownSpec. B cells blue
Spec T cell brownSpec B cell blue
OVA-HELconjugate
OVA + HEL
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)
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.
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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 expressioninduces 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 GCmay play a role in auto-antibody
production• IL-6: Induces B cell proliferationinduces B cell differentiation
increase IgG production
Co-stimulatory molecules are required for GC formation:CD40/CD40L, CD28 and ICOSMembers of the TNF family are also required
Immunol. Rev. 156:127, 1997
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 primaryClosed square: late primaryDiamond: secondaryTriangle: tertiary
Affinity of Ab increases witheach immunization and so does the number of mutations
Fundamental Immunology TextbookEditor W.E. Paul
Mutations are clustered in the CDRs and contribute to the increase in affinity.
Fundamental Immunology TextbookEditor W.E. Paul
Location of cells in GC determined by chemokinesCXCL13 in light zone attracts CXCR5+ T and B cellsCXCL12 in dark zone attracts CXCR4+ B cells
Figure 9-15
Trends Immunol. 22:361, 2001
Immunity 30, March 20, 2009, Fazilleau et al
Figure 9-10
