ESF workshop Leeds. ESF workshop Leeds Plasma cells Activators: Blimp-1, XBP1 Repressors: Pax5, Bcl6 BCR and CD40 signalling Cytokines: IL-6, -10,

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Presentation transcript:

ESF workshop Leeds

Plasma cells Activators: Blimp-1, XBP1 Repressors: Pax5, Bcl6 BCR and CD40 signalling Cytokines: IL-6, -10, -21 TLRs (TLR4, TLR9) MicroRNAs : miR-155 BIC

B cell activation and formation of plasma cells Shapiro-Shelef & Calame (2005) Nat. Rev. Immunol. 5: 230-242.

Transcriptional regulation of plasma cell differentiation Nera & Lassila (2006) Scand. J. Immunol. 64: 190-199.

Pax5 Bcl6 Paired box protein Groucho, HDACs Guardian of B cell identity and function B cell commitment -crucial for B cell fate Represses plasma cell formation Proto-oncogene BTB/POZ Zn finger repressor (HDACs) Required for GC formation Tolerance for genotoxic stress (p53, ATR) Represses plasma cell formation Proto-oncogene

Blimp-1 / PRDI-BF1 (prdm1) Zn finger repressor HDAC Master regulator of plasma cell formation B cells can initiate plasma cell differentiation without Blimp-1 upregulation 5-15 % of GC B cells are Blimp-1+ and Bcl6- Long lived plasma cells need Blimp-1 Blimp-1 is suggested not to be required for memory B cell formation

AID (Aicda) Activation induced cytidine deaminase Needed for somatic hypermutation, class switch recombination and gene conversion transcriptional regulation (Pax5, E2A) intracellular compartmentalization posttranslational modification posttranscriptional regulation (miR-155/Bic) UNG Uracil-DNA glycosylase

Durandy et al. (2005). Immunol. Rev.203: 67-79.

Todd et al Nature Rev. Immunol 8, 663-674, 2008

Disruption of Pax5 in DT40 B cells Nera et al. (2006) Immunity 24: 283-93.

Slow growth and decreased sIgM expression Log Fluorescence Intensity Nera et al. (2006) Immunity 24: 283-93.

Defective BCR signaling in the absence of Pax5 BCR cross-linking H2O2 Nera et al. (2006) Immunity 24: 283-93.

Loss of Pax5 promotes plasma cell differentiation Nera et al. (2006) Immunity 24: 283-93.

Conclusions Loss of Pax5 promotes plasma cell differentiation Pax5 target genes include components of BCR signalling, Ig diversification (AID) and Ig secretion (XBP-1) Pax5 positively regulates B cell identity as well as GC B cell program Pax5 represses indirectly Blimp-1 via Bcl6

Nera & Lassila (2006) Scand. J. Immunol. 64: 190-199.

Nutt et al. (2007) Nat. Rev. Immunol. 7: 923-927

Interaction / repression Bcl6 BTB/POZ (bric-a-brac, tramtrack, broad complex/poxvirus and Zn domain family) Bcl6 Interaction / repression DNA binding F1 F2 F3 F4 F5 F6 BTB/POZ Structure N - - C IRF4 BCoR Evi-9 PLZF BAZF SMRT Sin3A HDAC Jun Miz-1

Bcl6 Master regulator of GC transcriptional programme Facilitates Ig affinity maturation (SHM, CSR) DNA damage sensing by regulating p53,ATR Repress plasma cell diffrentiation via Blimp1 Inhibition of memory B cell formation

Control of PC differentiation Martins & Calame (2008) Ann Rev Immunol. 26: 133-69.

Disruption of Bcl6 in DT40 B cells A p1 p2 deleted bsr-F neo-F F1 Bcl6-bsr Bcl6-neo bsr neo Bcl6 gene R2 WT Bcl6 +/- Bcl6 -/- bsr neo Bcl6 Relative number of transcripts WT Bcl6-/- Bcl6-/- /Bcl6 B C

Slow growth and decreased sIgM expression B sIgM CD45 WT Bcl6-/- Bcl6-/- /Bcl6 Log Fluorescence Intensity 101 103 Time (h) Cell density (x106/ml)

Bcl6 downregulation leads to plasma cell differentiation WT Bcl6-/- 0 min 0.5 h 1 h 2 h 4 h Ig µ Ig λ 23

Loss of Bcl6 downregulates EBF and Pax5 but upregulates E2A expression

AID and UNG require Bcl6 expression and Bcl6 represses Blimp-1

Conclusions Bcl6 downregulation leads to exit from GC program and differentiation into plasma cells Loss of Bcl6 supresses the plasma cell repression function of Pax5 and MITF Bcl6 controls double stranded DNA breaks by allowing AID, UNG, RAD54, BRCA2 expression and thus SHM, CSR and gene conversion. 4. Bcl6 target genes include components of BCR signalling, Ig diversification and secretion Bcl6 is a direct repressor of Blimp-1

Todd et al Nature Rev. Immunol 8, 663-674, 2008

H. Singh Nat Immunol 8,119, 2006

Laslo et al Cell 2006