Adaptive immunity 2 - Immune regulatory mechanisms through B cell axis

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©2015 Osaka University. All rights reserved. Immune regulatory mechanisms through B cell axis Tomohiro Kurosaki Osaka University Adaptive Immunity 2 Number 1 Number 2 Number 3 Antigen presenting cell Helper T cell inflammatory cytokine (IL-6,M1P1α,M1P1) inflammatory cytokine T cell activation B cell 1

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  1. 1. 2015 Osaka University. All rights reserved. Immune regulatory mechanisms through B cell axis Tomohiro Kurosaki Osaka University Adaptive Immunity 2 Number 1 Number 2 Number 3 Antigen presenting cell Helper T cell inflammatory cytokine (IL-6,M1P1,M1P1) inflammatory cytokine T cell activation B cell 1
  2. 2. 2015 Osaka University. All rights reserved. Inflammatory cytokine (IL-6,M1P1,M1P1) Anti-inflammatory cytokine (IL-10) Breg cells in mice 2
  3. 3. 2015 Osaka University. All rights reserved. DTH: Delayed-type hypersensitivity EAE: Experimental autoimmune encephalomyelitis IBD: Inflammatory bowel diseases MS: Multiple sclerosis SLE: Systemic lupus erythematosus Year Mouse Human 1974 B cells suppress DTH (Katz SI et al., Nature) 1996 B cell-deficient mice develop EAE (Wolf SD et al., J. Exp. Med.) 2002 IL-10+/+ B cells suppress EAE (Fillatreau S et al., Nature Immunol.) B cells control IBD (Mizoguchi A et al., Immunity) 2007 B cells have an impaired IL-10 production in MS (Duddy M et al., J. Immunol.) 2010 B cells have an impaired IL-10 production in SLE (Blair PA et al., Immunity) Highlights in regulatory B cell research DTH: Delayed-type hypersensitivity EAE: Experimental autoimmune encephalomyelitis IBD: Inflammatory bowel diseases MS: Multiple sclerosis SLE: Systemic lupus erythematosus Year Mouse Human 1974 B cells suppress DTH (Katz SI et al., Nature) 1996 B cell-deficient mice develop EAE (Wolf SD et al., J. Exp. Med.) 2002 IL-10+/+ B cells suppress EAE (Fillatreau S et al., Nature Immunol.) B cells control IBD (Mizoguchi A et al., Immunity) 2007 B cells have an impaired IL-10 production in MS (Duddy M et al., J. Immunol.) 2010 B cells have an impaired IL-10 production in SLE (Blair PA et al., Immunity) Highlights in regulatory B cell research 3
  4. 4. 2015 Osaka University. All rights reserved. Wolf SD et al. J. Exp. Med. 184: 2271-2278,1996 Data from individual mice were plotted from three consecutive B10.PL (squares) (B) and four consecutive B10.PLMT (circles) (C) mice. The data was collected from one fifth of the experiments set up. DiseaseSeverity DTH: Delayed-type hypersensitivity EAE: Experimental autoimmune encephalomyelitis IBD: Inflammatory bowel diseases MS: Multiple sclerosis SLE: Systemic lupus erythematosus Year Mouse Human 1974 B cells suppress DTH (Katz SI et al., Nature) 1996 B cell-deficient mice develop EAE (Wolf SD et al., J. Exp. Med.) 2002 IL-10+/+ B cells suppress EAE (Fillatreau S et al., Nature Immunol.) B cells control IBD (Mizoguchi A et al., Immunity) 2007 B cells have an impaired IL-10 production in MS (Duddy M et al., J. Immunol.) 2010 B cells have an impaired IL-10 production in SLE (Blair PA et al., Immunity) Highlights in regulatory B cell research 4
  5. 5. 2015 Osaka University. All rights reserved. Fillatreau S. et al., Nature Immunol. 10, 944-950, 2002 IL-10-producing B cells suppress EAE development Clinicalscore Time (d) IL-10-/- B cells B6 B cells T2-MZP BREG cell B10 cell IgMhigh IgMhigh CD21high CD21high CD24high CD24high CD1dhigh CD1dhigh CD19CD19 5
  6. 6. 2015 Osaka University. All rights reserved. DTH: Delayed-type hypersensitivity EAE: Experimental autoimmune encephalomyelitis IBD: Inflammatory bowel diseases MS: Multiple sclerosis SLE: Systemic lupus erythematosus Year Mouse Human 1974 B cells suppress DTH (Katz SI et al., Nature) 1996 B cell-deficient mice develop EAE (Wolf SD et al., J. Exp. Med.) 2002 IL-10+/+ B cells suppress EAE (Fillatreau S et al., Nature Immunol.) B cells control IBD (Mizoguchi A et al., Immunity) 2007 B cells have an impaired IL-10 production in MS (Duddy M et al., J. Immunol.) 2010 B cells have an impaired IL-10 production in SLE (Blair PA et al., Immunity) Highlights in regulatory B cell research Duddy M et al. J Immunol. 178: 6092-6099, 2007 IL-10 Cytokinesecretion(pg/ml) CD40 alone Dual Stimulation p=0.008 p=0.037 Normal Multiple Sclerosis 6
  7. 7. 2015 Osaka University. All rights reserved. CD19+CD24hiCD38hi B cells from SLE patients express lower amounts of IL-10 CD24hi CD38hi CD24hi CD38hi CD24hi CD38int CD24hi CD38- CD24hi CD38- CD24hi CD38int Blair P.A. et al, Immunity 32, 129-140, 2010 Healthy SLE CD19+CD24hiCD38hi B cells from healthy human individuals suppress T helper cell differentiation through IL-10 :CD24hiCD38hi B Cells Blair P.A. et al, Immunity 32, 129-140, 2010 7
  8. 8. 2015 Osaka University. All rights reserved. Th17 cells Th1 cells Antigen TLR ligand TLR BCR CD40 MHCII TCR B10 cells Activated B10 cells CD4+ T cells CD40 IL-10 IL-17 IFN- CD40L MHCII The model of regulatory B cell development Mauri, C. et al., Annu. Rev. Immunol., 30:221-241, 2012. Yoshizaki, A., et al., Nature, 491:264-268, 2012. Our working model 8
  9. 9. 2015 Osaka University. All rights reserved. What lineage of B cell is producing IL-10 in vivo ? Lymph node B cells FAS+GL7+B cells (GC B) CD138+CD44+ cells are main IL-10-producing B cells IL-10-Venus B220+ cells CD138+CD44+ cells IL-10-Venus Nave mice (day 0) EAE-induced mice (days 14) B220+ cells WT mice IL-10-Venus mice Matsumoto M. et al, Immunity 41, 1040-1051, 2014 9
  10. 10. 2015 Osaka University. All rights reserved. Draining LN cells 0 2 4 6 8 10 12 days 0 days 7 days 14 days 21 days 28 Cells(x104) Gated on CD138+CD44+ cells Blimp1-GFP EAE-induced Blimp1-GFP mice CD138 Plasmablast (Blimp1int) CD138+CD44+ cells in dLN are plasmablasts Matsumoto M. et al, Immunity 41, 1040-1051, 2014 Oracki, S. A. et al., Immunol. Review, 237:140-159, 2010 Blimp1 is a master gene to differentiate into CD138+ plasmablasts and plasma cells Activated B cell Plasmablast Short-lived Plasmablast Long-lived Plasmablast Surface lg+ B220+ Synd-1- Flt3+ MHC ll++ CXCR4- Pax5+++ Irf4+ Surface lg+ B220 lo Synd-1+ Flt3- MHC ll+ CXCR4+ Pax5- Irf4+++ Blimp-1+ Surface lg- B220- Synd-1+ Flt3- MHC ll- CXCR4+++ Pax5- Irf4+++ Blimp-1+++ Surface lg- B220- Synd-1+ Flt3- MHC ll+ CXCR4++ Pax5- Irf4+++ Blimp-1++ (CD138+) 10
  11. 11. 2015 Osaka University. All rights reserved. EAEscore Days Blimp1 BKO mice exhibit increased severity of EAE 0 1 2 3 4 5 0 10 20 30 MBC mbprdm1 P