Stage I Stage II Stage III Stage IV

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1 Harvard-MIT Division of Health Sciences and Technology HST.176: Cellular and Molecular Immunology Course Director: Dr. Shiv Pillai Stage I Stage II Stage III Stage IV Receptor gene Rearrangement Elimination of self-reactive cells Responders Effectors

2 3. BCR MEDIATED MAINTENANCE Y Y FOLLICLE Y SPLEEN 1. pre-bcr MEDIATED POSITIVE SELECTION 2. BCR MEDIATED EMIGRATION BONE MARROW Early pro-b Intermediate pro-b Late pro-b Ψ Large pre-b pre-bcr Small pre-b Y Immature B YY Mature B A B C C' D E F IgM IgD D H to J H rearrangement V H to DJ H V L to J L rearrangement rearrangement

3 Positive selection I Pre-B receptor dependent XLA Syk KO µko Negative selection and Receptor editing Positive selection II Pre-pro B Pro-B I Pro-B2/preB A B C C' Ψ D Y Y E PERIPHERY Y Y F Large pre-b Small Pre-B Immature B Mature B V to DJ out of frame

4 HSC Pre-B receptor expressing cells proliferate and allelically exclude VDJ+ In-frame C' Large pre-b VDJ+ In-frame IL-7 SDF-1 IL-7 SDF-1 IL-7 C' Large pre-b Common lymphoid progenitor A pre-pro-b D-J H B pro-b V-DJ H C pro/pre-b VDJ+ In-frame C' Large pre-b VDJ+ In-frame VDJ- VDJ- C' Large pre-b

5 Commitment Positive selection I Allelic exclusion Positive selection II Negative selection T B

6 Transcriptional regulation of early lymphoid development Tcf-1 -/- Gata-3 -/- DN DP SP Ikaros -/- CLP E2a -/- PU.1 -/- Sox-4 -/- Ebf -/- ProB PreB B Pax-5 -/-

7 Entry versus commitment Commitment implies irreversibility and in wild type B cells has occurred when Ig H-chain gene rearrangement is initiated Certain transcription factors such as EBF and E2A are required to turn on genes required early in B cell development In the absence of Pax-5 cells enter the B lineage but remain highly plastic

8 Pre-B receptor B cell receptor ι/vpreb ω/λ5 Ig β Ig α Ig β Ig α Syk ITAM Syk ITAM Blk/Lyn/Fyn (Src family kinases) Blk/Lyn/Fyn/Fgr (Src family kinases) Btk Other signaling pathways Btk (Bruton's tyrosine kinase) Defective in X-linked agammaglobulinemia) Other signaling pathways

9 ι/vpreb ω/λ5 Ig β Ig α Syk ITAM Blk/Lyn/Fyn Btk 1)Survival 2) Proliferation 3) Allelic exclusion 4) Induction of κ rearrangement 5) Shut off of surrogate light chain expression

10 B cell tolerance See Immunobiology, by Janeway,C., Travers, P., Walport, M. and Capra, J., Garland Publishing, 5th edition, 2001 & Cellular and Molecular Immunology by Abbas, A., Pober, J., and Lichtman, A., W B Saunders; 4th edition.

11 RECEPTOR EDITING Rag gene reexpression Deletion of old V κ-jκ rearrangement New κ or λ lightchain CLONAL DELETION BCR signals induce caspase activation Apoptotic death Multivalent Paucivalent OR ANERGY Chronic crosslinking model Ca++ influx seen but not sustained NFAT and ERK activated normally NFκB and JNK NOT activated

12 Red Pulp White pulp B T B marginal zone and marginal sinus

13 L VDJ µ Poly A sites δ Poly A sites AAAA Cap site ATG Unspliced IgD message AAAA mrna for IgD heavy chain AAAA mrna for IgM heavy chain

14 monosaccharide polysaccharide antigen receptor NO SIGNAL SIGNAL TRANSDUCTION

15 Microbial antigens Bacterial LPS B-1 Y? Microbial antigens HSC pro-b/ pre-b IgM YY B IgD Y B-1 Fetal Liver HSC No TdT Limited diversity B cells with bias towards multivalent TI-1 antigens Y B-1 B-1 cells are self-renewing and express CD5 The B-1/CD5 B "lineage"

16 THREE DISTINCT TYPES OF PERIPHERAL B LYMPHOCYTES CD21 HIGH Y IgM CD1 SPLEEN PERITONEUM / MUCOSAL SITES MARGINAL ZONE B CELLS B-1 B CELLs IgM Y CD5 FOLLICULAR B CELLS IgM IgD YY CD21

17 MZ and Follicular B cells See Immunobiology, by Janeway,C., Travers, P., Walport, M. and Capra, J., Garland Publishing, 5th edition, 2001 & Cellular and Molecular Immunology by Abbas, A., Pober, J., and Lichtman, A., W B Saunders; 4th edition.

18 Are only chosen B cells selected by endogenous antigens? OR Do all B cells get tickled via the antigen receptor?

19 Mutation Signal Strength MZ FO B-1 BCR BCR "No BCR signals" Other pathways Btk Btk "Weak BCR signals" Other pathways PLCγ2 PLCγ2 "Weak BCR signals" +* - - Other pathways PKCβ PKCβ " Weak and Intermediate BCR signals" None "Weak, Intermediate, and Strong BCR signals" + + +

20 LONG-LIVED PERIPHERAL B CELL POPULATIONS Strong BCR Signals.B-1 cells Intermediate strength BCR signals.follicular B cells Relatively weak BCR signals..mz B cells

21 CD21 CD1 Y MZ B CELLS IgM Y Y IgD Y IgD FI Newly formed B cells SPLEEN Y FIII NF FII FOLLICLE pre-bcr MEDIATED POSITIVE SELECTION BCR MEDIATED EMIGRATION BONE MARROW Early pro-b Intermediate pro-b Late pro-b Ψ Large pre-b pre-bcr Small pre-b Y Immature B Y Mature B A B C C' D E F IgM? IgD D H to J H rearrangement V H to DJ H rearrangement V L to J L rearrangement

22 activated T TCR CD4 gp 39/CD40L Y BCR MHC class II (loaded) CD40 Y B

23 T cell areas follicle (B cell zone) Cortex Medulla afferent lymphatics artery vein efferent lymphatic 1.Dendritic cells (interdigitating) in T cell zones 2. Follicular dendritic cells in B cell areas 3. Macrophages everywhere

24 Red pulp 2 Focal aggregate X Y I Ag T Y Y 3 Germinal center B 4 White pulp

25 T B somatic mutation isotype switching T high affinity T cell Memory B cells low affinity APC X?Receptor diversification and rescue Follicular Dendritic cell Plasma cells

26 Activation of APCs via CD40 to release IL-12 and drive a TH1 type response CD40 T activated gp 39/CD40L?Signals to T cell TCR CD4 gp 39/CD40L Y BCR Y MHC class II (loaded) B CD40 Required for T-dependent immune responses -proliferation -class switching -germinal center formation -somatic mutation CD40L mutations lead to X-linked hyper-igm syndrome

27 PALS (T cell area) Follicle ( B cell area) Dark zone Light zone } Germinal center memory B cells plasma cells Centroblasts Centrocytes apoptosis V gene hypermutation

28 JH Cµ Cδ Cγ3 Cγ1 Cα1 Cγ2 Cγ4 Cε Cα2

29 VDJ Sµ Cµ Cδ Sγ3 Cγ3 Sγ1 Cγ1 Sα Cα γ2b, γ2a and ε Sγ3 Cγ3 Cδ Sγ1 VDJ Cµ Cγ1 Looping out and deletion Sµ Sα Cα VDJ Sα Cα Switched to IgA

30 Switch regions and I-region promoters VDJ C ienh Iµ Sµ µ δ γ3 α Iα Sα Iγ3 Sγ3 Cα3'E 3'αE HS3B HS4 γ2b, γ2a and ε C regions LCR Iµ Sµ µ unspliced pre-mrna Iµ µ spliced Iµ transcript

31 Class Switching (Murine) 1. IL-4 promotes switching to IgG1 and IgE 2. TGF- β promotes switching to IgA 3. γ-ifn promotes switching to IgG2a

32 Somatic mutation-i 1. Point substitutions. Non-templated single base changes in rearranged H- and L-chain V region genes 2. Requires T cell help, occurs in centrocytes to 10-3 base pairs/generation 4. Bell shaped curve of mutations starts in leader intron and ends about 1.5 kb downstream 5. Hotspot motifs 6. Transitions more common than transversions

33 SOMATIC MUTATION -II 7. Requires enhancer 8. Mechanism:AID DEPENDENT DNA DEAMINATION a. Cytosines converted to uracils b. Replication or error prone repair generates mutations 9. Accessibility?? Need for transcription??

34 AID required for both class switching and somatic mutation AID is a novel Activation induced cytidine deaminase Related to a protein involved in RNA editing Required for class switching and also for somatic mutation Aid-/- mice have large germinal centers Humans lacking AID present with hyper IgM syndrome

35 3. BCR MEDIATED MAINTENANCE Y Y FOLLICLE Y SPLEEN 1. pre-bcr MEDIATED POSITIVE SELECTION 2. BCR MEDIATED EMIGRATION BONE MARROW Early pro-b Intermediate pro-b Late pro-b Ψ Large pre-b pre-bcr Small pre-b Y Immature B YY Mature B A B C C' D E F IgM IgD D H to J H rearrangement V H to DJ H rearrangement V L to J L rearrangement

36 For more information and examples, see Immunobiology, by Janeway,C., Travers, P., Walport, M. and Capra, J., Garland Publishing, 5th edition, 2001 & Cellular and Molecular Immunology by Abbas, A., Pober, J., and Lichtman, A., W B Saunders; 4th edition.

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