b/t cell interaction march 26, 2007
TRANSCRIPT
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Properties of primary and secondary B cell response
Type of B cellNaive B cell Memory
B cellprimary response
Secondary responseInduction slow rapidFrequency 1:104 1:103
Ig isotype IgM > IgG IgG, IgAAffinity of antibody low highSomatic hypermutation low high
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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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Figure 9-4
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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
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Spec. T cells blueB cells brown
T cells brownSpec. B cells blue
Spec T cell brownSpec B cell blue
OVA-HELconjugate
OVA + HEL
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T cell cytokines influence Ig class swtiching
B
DC Th0
IL-6
IL-4
Th2
IL-4IL-5
IgG1 (IgG4)IgA, IgE
IL-4,IL-10,IL-13
Extracellular toxins,Worms, allergens
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IntracellularBacteria, viruses
NK
IgG2a (IgG1, IgG3)
BIL-12
Th1DC Th0
IL-2IFN-
Mac-act
IFN-
IFN-
IL-12
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Figure 9-6
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Figure 9-7
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Figure 9-19
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Trends Immunol. 23:31, 2002
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Cytokines act to stimulate transcription at switch locus.
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Th1 cytokines: effects on B cells
• IL-2: stimulates proliferation
• IFN-: Inhibits proliferation
Downregulates MHC expressionInduces isotype
switching
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Th2 cytokines: effects on B cells
• IL-4: Stimulates proliferationupregulates MHC expressioninduces isotype switching
• IL-10: Stimulates proliferationupregulates MHC expressioninduces B cell differentiation
• IL-5: induces isotype switching• IL-13: similar effect to IL-4 on human B cells no effect on mouse B cells
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Th3 cytokines: effects on B cells
• IL-10: Stimulates proliferationupregulates MHC expression
induces B cell differentiation
• TGF-: inhibits proliferationinduces switch to IgA
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Immunol. Rev. 211:255, 2006
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Figure 9-12 part 1 of 2
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Germinal Center Reaction
• Initial contact between B and T cells occurs in T cell area - isotype switch signal
• Activated T and B cells migrate to the follicle - initiate germinal center. Only T and B cells recognizing the same antigen are present in GC - clonal populations
• 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
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Specialized T cell migrates to GC.CD4+, CD45R0+, CXCR5+Secretes IL-2 and IL-10 and does notappear to be traditional Th2 cells
J. Exp. Med. 192:1545, 2000
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Nat. RevImmunol5:853, 2005
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Co-stimulatory molecules are required for GC formation:CD40/CD40L, CD28 and ICOS
Nature 409:105, 2001
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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
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CDR1, 2, 3 of Ab molecule contact antigen
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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
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Mutations are clustered in the CDRs and contribute to the increase in affinity.
Fundamental Immunology TextbookEditor W.E. Paul
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Figure 9-14
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Location of cells in GC determined by chemokinesCXCL13 in light zone attracts CXCR5+ T and B cellsCXCL12 in dark zone attracts CXCR4+ B cells
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Figure 9-15
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Trends Immunol. 22:361, 2001
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CD21 and FcRIIB on FDC is required for Ab production
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Nat. RevImmunol5:853, 2005
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Fundamental Immunology
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Immunol. Rev. 211:255, 2006
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Figure 9-10
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Secondary response
Immunol. Rev. 211:255, 2006