B/T cell interaction

March 26, 2007Penny Morel

4-0343, morel@pitt.edu

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