Normal GC initiation then collapse; normal mutation and 10. Constitutive signalling leads to spontaneous GC in PP, even BCR -/- 19

Transcription

1 S1 Genetic modifications affecting germinal-centre formation and function Gene Compartment GC Phenotype Ref LTα, LTβ, TNF, Organ Disorganized lymphoid architecture in spleens; poor 1 TNFRI, LTβR architecture segregation of B and T cells; no FDC development CXCR5 -/-, No segregation of B and T cells 2 CXCL13 -/- Nkx2.3 -/- Disorganized spleen; poor GC development; disorganized 3 ASC foci BAFF -/- Poor GC development due to FDC defects 4 CR2 -/- (CD21) B-cell Normal formation and resolution of GC; reduced bone marrow 5 intrinsic ASC production BCMA -/- Normal GC formation; reduced bone marrow ASC 6 BCL-2 or BCL- Normal GC formation; defective selection against low affinity 7,8 X L cells CD45 -/- Normal GC initiation then collapse; normal mutation and 9 selection in CD45 -/- B-cell chimeras SPI-B -/- Normal GC initiation then collapse; normal mutation and 10 selection BAFFR -/- Normal GC initiation then collapse; reduced B-cell 4 proliferation MSH2 -/- Initiate GC; collapse due to apoptosis; normal mutation 11 CD19 -/- GC initiation but no progression; survival or proliferation 12 defect BLIMP1 -/- Enlarged GC; no plasma cells 13 Aiolos -/- Enlarged GC; diminished mutation and selection; no bone 14 marrow ASC AID -/- Enlarged GC; no isotype switching or mutation 15 BCL6 Constitutive GC; possibly diminished ASC 16 GANP Enlarged GC; heightened positive selection 17 PKCδ -/- Constitutive GC; B-cell hyper-proliferation and increased IL-6 18 LMP1 Constitutive signalling leads to spontaneous GC in PP, even BCR -/- 19

2 RGS1 -/- Constitutive GC; abnormal ASC localization; normal affinity 20 maturation BCL6 -/- No GC but IgM and IgG memory is formed without mutation 21 OBF1 -/-, OCT2 -/- No GC alone or in double knockout 22 C3 -/- or C4 -/- Greatly reduced GC and IgG antibody due to failure to 23 activate B cells GANP -/- No GC 24 PI3Kδ -/- No GC after immunization 25 CD28 -/- T-cell No GC; defective T-cell priming 26 SAP -/- intrinsic No GC; defective cytokine production by T cells? 27 IKK2 -/- No induced GC; CD4 + T-cell intrinsic 28 VAV1 -/- No GC and no ASC, possibly due to reduced cytokine 29 production NFATp -/- Spontaneous, large GC in spleen with age 30 PEP -/- Enhanced activation of LCK in effector/memory T cells with spontaneous GC and elevated serum antibody 31 ICOS -/- B-T No GC, cytokine mediated? 32 ICOSL -/- interaction MHC class II -/- No GC; defective CD4 + T cells and antigen presentation 33 CD80 -/- CD86 -/- No GC; T-cell priming as well as B T interaction affected. 32 CD40 -/- CD40L -/- No GC 34,35 c-rel/nf-κb Compound No GC; combined B, T and architectural problems 36 NF-κB p52 & FDC and haematopoietic problems 36 BCL3 IL-6 -/- Small GC, stromal-derived IL IL-4 -/- IL-21R -/- No GC after immunization in double mutant. 38 AID, activation-induced cytidine deaminase; ASC, antibody-secreting cell; BAFF, B-cell-activating factor; BAFFR, BAFF receptor; BCL, B- cell lymphoma; BCMA, B-cell maturation antigen; BCR, B-cell receptor; BLIMP, B-lymphocyte-induced maturation protein; CR2, complement receptor 2; CXCL, CXC-chemokine ligand; CXCR, CXC-chemokine receptor; FDC, follicular dendritic cell; GANP, germinal centre-associated

3 nuclear protein; GC, germinal centre; ICOS, inducible T-cell co-stimulator; ICOSL, ICOS ligand; IL, interleukin; IKK, inhibitor of NF-κB kinase; LMP1, latent membrane protein 1; LT, lymphotoxin; LTβR, LTβ receptor; MSH2, homologue 2 of E. coli MutS; NFAT, nuclear factor of activated T cells; NF-κB, nuclear factor-κb; Nkx2.3, NK2 transcription-factor related, locus 3; OBF, OCT-binding factor; OCT, octamerbinding transcription factor; PEP, PEST-domain-enriched PTP; PI3K, phosphatidylinositol 3-kinase; PP, Peyer s patch; PKC, protein kinase C; RGS1, regulator of G protein signalling 1; SAP, signalling lymphocytic activation molecule (SLAM)-associated protein; TNFR, tumour-necrosis factor receptor. 1. Mebius, R. E. & Kraal, G. Structure and function of the spleen. Nature Rev Immunol 5, (2005). 2. Cyster, J. G. Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs. Annu. Rev. Immunol. 23, (2005). 3. Tarlinton, D. et al. Architectural defects in the spleens of Nkx2-3-deficient mice are intrinsic and associated with defects in both B cell maturation and T cell-dependent immune responses. J. Immunol. 170, (2003). 4. Rahman, Z. S. et al. Normal induction but attenuated progression of germinal center responses in BAFF and BAFF-R signaling-deficient mice. J. Exp. Med. 198, (2003). 5. Carroll, M. C. The role of complement in B cell activation and tolerance. Adv. Immunol. 74, (2000). 6. O'Connor, B. P. et al. BCMA is essential for the survival of long-lived bone marrow plasma cells. J. Exp. Med. 199, (2004). 7. Takahashi, Y. et al. Relaxed negative selection in germinal centers and impaired affinity maturation in bcl-xl mice. J. Exp. Med. 190, (1999). 8. Smith, K. G. et al. bcl-2 transgene expression inhibits apoptosis in the germinal center and reveals differences in the selection of memory B cells and bone marrow antibody-forming cells. J. Exp. Med. 191, (2000). 9. Huntington, N. D. et al. CD45 links the B cell receptor with cell survival and is required for the persistence of germinal centers. Nature Immunol. 7, (2006). 10. Su, G. H. et al. Defective B cell receptor-mediated responses in mice lacking the Ets protein, Spi-B. J. EMBO 16, (1997). 11. Vora, K.A. et al. Severe attenuation of the B cell immune response in Msh2-deficient mice. J. Exp. Med. 189, (1999). 12. Wang, Y. & Carter, R. H. CD19 regulates B cell maturation, proliferation, and positive selection in the FDC zone of murine splenic germinal centers. Immunity 22, (2005). 13. Shapiro-Shelef, M. et al. Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity 19, (2003).

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