b/t cell interaction march 26, 2007
TRANSCRIPT
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
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)
Figure 9-4
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
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
IntracellularBacteria, viruses
NK
IgG2a (IgG1, IgG3)
BIL-12
Th1DC Th0
IL-2IFN-
Mac-act
IFN-
IFN-
IL-12
Figure 9-6
Figure 9-7
Figure 9-19
Trends Immunol. 23:31, 2002
Cytokines act to stimulate transcription at switch locus.
Th1 cytokines: effects on B cells
• IL-2: stimulates proliferation
• IFN-: Inhibits proliferation
Downregulates MHC expressionInduces isotype
switching
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
Th3 cytokines: effects on B cells
• IL-10: Stimulates proliferationupregulates MHC expression
induces B cell differentiation
• TGF-: inhibits proliferationinduces switch to IgA
Immunol. Rev. 211:255, 2006
Figure 9-12 part 1 of 2
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
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
Nat. RevImmunol5:853, 2005
Co-stimulatory molecules are required for GC formation:CD40/CD40L, CD28 and ICOS
Nature 409:105, 2001
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
Figure 9-14
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
CD21 and FcRIIB on FDC is required for Ab production
Nat. RevImmunol5:853, 2005
Fundamental Immunology
Immunol. Rev. 211:255, 2006
Figure 9-10
Secondary response
Immunol. Rev. 211:255, 2006