B cell differentiation: role of lympho-stromal interactions

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1 cell differentiation: role of lympho-stromal interactions Claudine Schiff November 2009

2 Hematopoiesis Days of Gestation Mutipotent progenitor HSC GATA 2 AML 1 GATA 3 c-myb Fetal Liver and one Marrow 15 Meg EGML Pu.1 18 Megacaryocytes E GML irth Erythrocytes G ML Ikaros Granulocytes M L Id2 Monocytes Notch1 Pax5 NK Lym phocytes Thymus T

3 cell differentiation IgM memory 2-Antigen dependent diversification T1 T2 MZ Spleen FO Somatic mutation Class sw itch Antigenic challenge follicle IgG,IgA or IgE Plasma cell Switched memory Transitional T1 M Mature naive 1-Antigen independent diversification New emigrants Spleen LN PP one marrow Pre-CR CR Stem cell CLP pro- Large pre- Small pre- Immat. Mature Mature naive recurcul. PC D H to J H V H to DJ H V L to J L

4 cell differentiation in the bone marrow

5 cell development depends on stromal cell interactions Cellular niches cell engagement Pre-CR checkpoint CR checkpoint Pre-CR CR 1990 Stem cell Pro- Pre-I Large pre-ii Small pre-ii immat. mature Trans. D H to J H V H to DJ H V L to J L Autoreactive Deletion Anergy R. editing Non autoreactive Periphery Kinetic in Ig gene rearrangements, tissue specificity, allelic exclusion

6 PAX5: : the guardian of cell identity and function

7 Transcription factors required for cell engagement pro-nk Id2 CLP pro- pre-i Stem cell Ikaros PU.1 lo E2A EF Notch-1 + Pax-5 PU.1 hi CMP pro-t

8 The pre-cr checkpoint Pre-CR CR Stem cell Pro- Pre-I Large pre-ii Small pre-ii immat. mature Trans. D H to J H V H to DJ H V L to J L Igµ UR VH #5 Vp UR SLC Pre-CR signaling Ig!/Ig" -->Proliferation -->Differentiation Y Y Y Y

9 How does the signal generate from the pre-cr? Constitutive activation pre-ii Ligand-induced signaling ligand in cis? pre-ii M stroma cell ligand in trans? Galectin-1 pre-ii

10 The galectin family Prototype Chimera Tandem CRD GAL1, 2, 5, 7, 10, 11, 13, 14 HSPC159 GAL3 GAL4, 6, 8, 9, 12. Soluble lectins that bind "-galactoside-containing glycans. Conserved Carbohydrate Recognition Domain and common structural fold. Found in vertebrates, invertebrates, and protists. Fifteen galectins in mammals classified in 3 categories. Involved in the regulation of innate and adaptive immune responses (cell activation, differentiation, cytokine secretion and apoptosis)

11 The pre-cr colocalizes with GAL1, VLA4 and LFA1 integrins at the pre-/stromal cell synapse Normal large pre-ii / OP9 co-cultures (220 + CD117 - c$ - ) Ig! GAL1!4 merge DIC Ig! GAL1 "1 merge DIC Ig! GAL1!L merge DIC Ig! GAL1 "2 merge DIC Frequency of cells w ith a relocalized pre-cr = 55% VLA4 (!4 "1) LFA1 (!L "2)

12 Synapse formation depends on the interactions between: - GAL1 and the pre-cr (#5UR) - GAL1 and VLA4, LFA1 integrins - VLA4, LFA1 and their stromal ligands ICAM, VCAM1 LFA1, VLA4 Stromal cell pre-ii cell pre-cr Gal1 Cell signaling Ig"/Ig# and lead to pre-cr activation Gauthier et al., PNAS, 2002 Rossi et al., J. Immunol, 2006 Espeli et al., lood, 2009

13 Formation for the pre-/stromal cell synapse Stromal cell pre- cell pre-cr GAL1 integrins ADAM-15 fibronectin GAL1, produced by stromal cells, binds to integrins and pre-crs GAL1 creates a physical link (a lattice) between the relocalizing pre- cell integrins, in contact with their stromal cell ligands, and the pre-crs

14 Stromal cell Synapse formation Pre-CR clustering and signaling pre- cell pre-cr GAL1 integrins ADAM-15 fibronectin Formation of the pre-/stromal cell synapse results in pre-cr clustering and signaling Espeli et al., Seminar Immunol, 2006 Rossi et al., JI 2006

15 Functional role of the pre-/stromal cell synapse: in vivo studies one marrow CD19+ CD19+IgM-CD23- WT GAL1 -/- CD CD IgM CD2 CD cell number (x10 5 ) Pro-pre-I Pre-II Imm. Recirc. WT KO No alteration of the cell differentiation in GAL1-/- mice

16 De novo pre- cell differentiation and proliferation d7 post HU Hydroxy-urea (HU) treated mice --> d2, d7 and d35 WT CD CD23 CD IgM GAL1 -/- CD19+IgM-CD CD2 CD25 Cell number (x10 5 ) Pro- pre-i 5 fold decrease p=0.022 * Pre-II Imm. Recirc. WT KO DNA content of pre-ii WT 42.9 KO 19.3 Impaired pre-ii cell differentiation Impaired pre-ii cell proliferation TO-PRO-3

17 Summary In vitro and in vivo studies indicate that lattice formation between pre-cr, GAL1 and integrins: - enhances pre-ii cell differentiation - enhances pre-ii cell proliferation Espeli et al., lood 2009

18 Cooperative effect of pre-cr signaling Constitutive activation (Tonic signaling) GAL-1 induced signaling In cis pre-ii Differentiation Proliferation pre-ii 220+ pro/pre-i Large pre-ii Small pre-ii IgM+ OP9 In trans GAL-1+ Differentiation Proliferation GAL1 "-actin pre-i

19 Lympho-stromal interactions during cell development in the bone marrow

20 M stromal cells niches for cell development HCS CXCL12 pro- pre-i IL7 GAL1 pre-ii HCS Nagasawa, Nat. Rev. Immunol., 2006 HSC move from bone surface or endothelial cells toward CXCL12+ stromal cells Differentiating HSC move along the processes of CXCL12+ cells and become pro- cells Pre-I cells reach IL7+ cells

21 Characterization of GAL1+ cells in the M GAL1 CD45 merge ONE ONE ONE Reticular cells Osteoblasts Hematopoietic cells GAL1 nucleus merge GAL1 nucleus merge GAL1 CD45 nucleus merge CD45- CD45- CD45+

22 A mouse model for the characterization of GAL1+ stromal cells in the M Lethal irradiation WT M Actin-gfp mice Chimeric mice Stroma GFP+ Hematopoietic cells GFP+ Stroma GFP+ Hematopoietic cells GFP-

23 Chimeric mice one section GFP GAL1 MERGE

24 Localization of large pre-ii cells in the M PKH26-labelling of pre-ii cells Injection to chimeric mice 24H in M Large pre-ii Stroma GFP+ GAL1

25 In summary GAL1+ stromal cells constitute a specific niche for large pre-ii cells HCS CXCL12 pro- pre-i GAL1 HCS IL7 Large pre-ii

26 cell differentiation in periphery

27 cell differentiation in spleen and lymph node IgM memory Immune response to c MZ Antigenic challenge IgG,IgA or IgE Plasma cell with high-affinity T2 FO follicle T1 Spleen Switched Memory with high-affinity Transitional T1 M Mature naiv e New emigrants Spleen LN PP one marrow Stem cell CLP pro- Large pre- Small pre- Immat. Mature Mature naive recurcul. PC

28 T-dependent follicular cell response Phase I Site of infection Ag -cell zone Primary follicle Phase I Ag Naiv e cell DC T-cell zone Agprimed DC Naiv e Th cell SYNAPSE I Th Th Th Th Th Th Th Agprimed Agprimed Th SYNAPSE II CD40 CD40L ICOSL ICOS Day 1 Day 7

29 T-dependent follicular cell response Phase II Site of infection Ag DC -cell zone T-cell zone Primary follicle Agprimed DC Naiv e Th cell SYNAPSE I Phase I Th Ag Th Th Th Naiv e cell Th Th Th Agprimed Th Agprimed SYNAPSE II Phase II Secondary follicle Th Plasma cell Day 1 Day 7 IgM PC short-lived and low-affinity PC, rapid initial response to pathogens

30 T-dependent follicular cell response Phase III Phase III Germinal center reaction Death Diversity FDC Th Selection Expansion Retention Memory GC Th GC SYNAPSE III Post GC Memory Pre-Plasma Memory Plasma cell Day 7 Positive selection of high affinity - cells: centrocytes + Ag (on FDC) + T FH High affinity --> no apoptosis Switched Memory and long-lived P with high-affinity

31 Lympho-stromal interactions during cell development in periphery

32 Lympho-stromal interactions in the lymph node zone T zone FDC Follicular dendritic cells FRC Follicular reticular cells Katakai et al., JEM, 2004 TNF! LT!1"2 LT!3 Follicular cell CXCR5 CXCR4 CD54 TNF-R CD106 FDC IL-6 CXCL13 CXCL12 Clusterin 8D6 HGF

33 Migration of follicular cell on FDC cells FDC ajénoff et al. Immunity, 2006 Fibroblastic Dentritic Cell (Gp38,aSM,Des) The conduit system asement membrane (LM511,411,332) Fibre Diameter 1-2mm Microfibril layer (ERTR-7) Collagen core (Coll I, III) Lokmic et al. Seminars in Immunol., 2008

34 Malignant cell homing in the bone marrow: lympho-stromal interactions

35 Follicular lymphoma Clinical features 2 nd most common adult lymphoma indolent but disseminated at presentation not curable with available treatments iological features germinal center -cell malignancy highly dependent on microenvironment cross-talk Etiology initiated in the bone marrow through t(14;18)! CL2 ++ t(14;18) found in blood of ~80% healthy individuals (variable frequencies)! FL-like Collaboration. Nadel

36 Is there M niches for FL-like cell migration and growth? FL cells develop in LN high incidence of M involvement MZ Somatic mutation Class sw itch IgG,IgA or IgE T2 FO Ag follicle GC Plasma cell T1 spleen T1 M FL FL-like one marrow Pre-CR CR Stem cell CLP pro- Large pre- Small pre- immat. mature mature D H to J H V H to DJ H V L to J L Recircu.

37 Transgenic Knock-out Knock-in In progress : search for FL-like niches in the M Do normal post-gc cells home to the M? Where? Germinal Center + Naive cell AID Post-GC cell M section Do FL-like cells home at the same location as their normal counterparts? Mouse model (Nadel s team): FL-like-gfp

38 L. Elantak F. Mourcin C. reton J.Tellier A. Anginot A. Jonquera S. Mancini M. Milili M. Espeli L. Chasson A. rouchet New comer: A. oned F. Guerlesquin, P. Roche and M. Feracci (ISM) - NMR studies F. Poirier (Jussieu) - GAL1 KO mice H. Karasuyama (Japan) - pre-cr function A. rouchet, PH Gourault and M Delisle (Toulouse) - bone tumors. Nadel s team, K. Tarte (Rennes), S. Valitutti (Toulouse). Reina (Strasbourg), N. Schleinitz and J. Hardw igsen (Marseille)- Follicular Lymphoma E. MacIntyre, V. Asnafi and K. eldord (Necker) - ALL G. Michel, H. Chambost, V. arlogis,. Roquelaure and D. Oliv e (Timone Hospital) - primary cell defects

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