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Lymphocyte Differentiation

Lymphocyte Differentiation. B cell development 、 activation and maturation. Genetic Models. Genetic models: Germ-Line model The genome contributed by the grem cells contains a large repertoire of immunoglobulin genes. No special genetic mechanisms to account for antibody diversity

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Lymphocyte Differentiation

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  1. Lymphocyte Differentiation

  2. B cell development、activation and maturation Genetic Models • Genetic models: • Germ-Line model • The genome contributed by the grem cells contains a large repertoire of immunoglobulin genes. • No special genetic mechanisms to account for antibody diversity • Somatic-Variation model • The genome contains a small number of immunoglobulin genes, from which a large number of antibody specificities are generated in somatic cells by mutation or recombination. • Two-Gene model, 1965 by W. Dryer and J. Bennett • Two separate genes encode a single immunoglobulin heavy and light chain, one gene for the V region and the other for the C region

  3. B cell development、activation and maturation Verification of the two-gene model 1967, by S. Tonegawa and N. Hozumi 1987, Tonegawa got Nobel Prize • Digested DNA fragemnts from embryonic and myeloma cells hybridized with radiolabel-RNA • (b) V and C gene are brought closer together and intervening DNA sequence is eliminated

  4. B cell development、activation and maturation Immunoglobulin Gene • 總共有7組基因片段 (gene segments) 進行重組後表現出免疫球蛋白。 • 重鏈： • V、D、J、C等4組基因片段。 • 位於第14條染色體。 • 具多段VH、多段DH、6段JH、9種CH（Cμ、Cδ、Cγ3、Cγ1、Cα1、Cγ2、Cγ4、Cε、Cα2）。 • 輕鏈（κ及λtype light chains）： • V、J、C等3組基因片段。 • κtype（多段Vκ、5段Jκ及單一段Cκ組成）位於第2條染色體。 • λtype（多段Vλ 、多段Jλ及多段Cλ組成）位於第22條染色體。

  5. Heavy Chain DNA κChain DNA λ Chain DNA B cell development、activation and maturation Immunoglobulin Germline Gene Segments in Human

  6. B cell development、activation and maturation Immunoglobulin Germline Gene Segments in Mouse

  7. B cell development、activation and maturation Heavy-Chain Gene Rearrangement in Human V-D-J joining

  8. B cell development、activation and maturation κ- Light-Chain Gene Rearrangement in Human V-J joining

  9. B cell development、activation and maturation λ- Light-Chain Gene Rearrangement in Human V-J joining

  10. B cell development、activation and maturation Heavy-Chain Gene Rearrangement in the mouse V-D-J joining

  11. B cell development、activation and maturation Kappa Light-Chain Gene Rearrangement in mouse V-J joining

  12. B cell development、activation and maturation

  13. B cell development、activation and maturation Overview • Antigen-independent phase • Immunocompetent B cells expressing membrane IgM and IgD are generated in the bone marrow • Antigen-dependent phase • B cells are activated and proliferated with secondary lymphoid organs • To differentiate into memory B cell and plasma cells

  14. B cell development、activation and maturation Differentiation of B cell

  15. B cell development、activation and maturation Differentiation of B cell • pro-B cell：重排heavy-chain genes（DH/ JH joining），沒有免疫球蛋白產物。 • pre-B cell：重排heavy-chain genes（VH /DH/ JH joining），將VDJ片段與Cμ連結，做出μpolypeptide；light-chain genes尚未重排。 • late pre-B cell：細胞表面具有完整的heavy chain、Ig-α、Ig-β及surrogate light chain • immature B cell：細胞表面具有完整的surface IgM（s IgM），此時細胞可以辨識抗原，與抗原結合後造成細胞部活化及消滅，無法再進入分化過程。

  16. B cell development、activation and maturation Differentiation of B cell • mature B cell：細胞表面具surface IgM、IgD（可對特殊抗體產生免疫反應）及其他表面分子，如： • 5’ nucleotidase（CD73）：鑲嵌於細胞膜的酵素。 • CD23：多醣蛋白（oligosaccharide-bing portein）。 • adhesion proteins：LFA-1、ICAM-1、CD22。 • L-selectin：surface homing receptor，引導細胞回到林巴結或到其他上皮細胞。 • MHC class II：呈獻抗原始T細胞認識。 • CD40：接受T細胞協助。 • 成熟B細胞未受刺激活化的細胞形態稱之為virgin B cell(naïve B cell)。 • 上述之B細胞發育在骨髓中進行，並無特殊抗原誘發屬於antigen-independent。當mature B cell進入secondary lymphoid organs後，因為抗原的誘導引其分化成為plasma cell而分泌游離之抗體（IgM）。

  17. B cell development、activation and maturation  

  18. B cell development、activation and maturation • Pro B-cells contact with stromal cells in the bone marrow • c-kit on pro B-cell interacts with stem-cell factor on surface of stromal cells • Pro B-cells begin to divide and differentiate into pre B-Cell • To express the receptor of IL-7 on the surface of pre B-Cell Back

  19. B-1 B cell Back

  20. B cell development、activation and maturation The Cell Cycle of B lymphocytes

  21. B cell development、activation and maturation B cell activation and maturation • B細胞活化主要因素： • Ig-α及Ig-β： • 連結B細胞表面抗體及細胞質內之protein tyrosine kinases（PTKs，CD45之細胞質內部domain具有此活性）。 • 抗原： • Thymus-dependent：B細胞與抗原（大部分之蛋白抗原）作用後，需受到T細胞的協助方可活化者；即B細胞表面分子CD40可與TH細胞表面分子CD40L（CD40 ligand）結合後啟動。

  22. B cell development、activation and maturation B cell activation and maturation • Thymus-independen：B細胞與抗原作用後，可自行分化產生抗體，不需受到T細胞的協助方可活化者；即B細胞可利用表面之IgM及IgD與抗原接觸後啟動B細胞增殖。 • T細胞刺激： • B細胞作為抗原呈獻細胞與TH細胞作用後，T細胞會釋放出helper factors活化B細胞。 • 被活化之B細胞表現出B7 proteins（T cell costimulators）並釋放出細胞激素（IL-6、TNFα）增加TH細胞活化作用的有效性。 • B細胞受到T細胞細胞激素作用或與T細胞接觸活化後，會以不同的路徑進行分化，分泌具專一性抗體。其中抗體isotype （class）switching會開始進行，轉形成IgG、IgA或IgE。

  23. B cell development、activation and maturation • Ig-α及Ig-β • Immunoreceptor tyrosine-based activation motif (ITAM) • The cytoplasmic tail of both Ig-α(61 amino acids ) and Ig-βlong (48 amino acids), 18-residue motif • To transduce the antigen-mIg binding stimulus into cell to become an effective intracellular signal • Binding stimulus is mediated by tyrosine kinases (PTKs) • The BCR itself has no PTK activity • Modification of coreceptors • B-cell coreceptor: • To provide stimulatory modifying signals • Complex of CD19, CR2 (CD21) and TAPA-1 (CD18) • CD22 • Associated with the B-cell receptor in resting B cells • A negative signal to make B-cell more difficult to activate

  24. B cell development、activation and maturation The initial stage of signal transduction by an activated BCR

  25. B cell development、activation and maturation • CD19: immunoglobulin superfamily protein, long cytoplasma tail, and three extracellular Ig-fold domain • CR2: receptor of complement (C3d) • TATP-1: transmembrane protein

  26. B cell development、activation and maturation • Thymus-dependent antigens (TD antigens) • Require to interact with TH cell • Thymus-independent antigens (TI antigens) • Not to require to interact with TH cell • Typ1, such as lipopolysaccharide of bacterial cell wall • Polyclonal B-cell activators • Activate immature and mature B cells • Fully T-cell independence • Type2, highly repetitious molecules, such as polymeric proteins • Not polyclonal B-cell activators • Activate mature B cells • need T-cell cytokines

  27. B cell development、activation and maturation Signals from TI and TD Antigens for B-cell Activation

  28. B-cell Activation by TD antigens

  29. The Humoral Responses- Primary and Secondary Response

  30. Class Switching • isotype （class）switching（同種形轉換）： • 在B細胞成熟（該時期遇抗原即發生）及增殖時發生。 • 利用heavy chain gene rearrangment來改變免疫球蛋白的類型（此時對於已經完成之VDJ joining比較不會受影響，即會表現出具有相同V區的基因，但此情形會因體細胞基因突變而增加抗體的多樣性）。 • T細胞及其分泌之激素對引發類別轉換具有重要的功能；如T細胞會傾向刺激IgA的形成，IL-4刺激B細胞產生IgG等。

  31. Plasma cell and Memory B cell • Plasma cell ： • Plasma cells會移入bone marrow中，因此marrow為人體plasma cell聚集最主要的場所也是循環免抗體的主要來源。 • Plasma cells 無法複製增生，生活期也只有幾天的時間。 • 細胞核具有鐘面。 • Memory B cell（記憶細胞）： • 因受抗原活化而產生，且記憶形成後會表現isotype抗體在其細胞表面上，具有循環特性，具有可引導淋巴細胞及組之間homing（自動引導）作用的表面分子。 • 分佈於各淋巴組織的發生中心，此處B細胞抗體可變區基因的變化率很大，選擇性也很高（過程中會使細胞進行自殺作用）。 • 多種記憶性B細胞會聚集於初級淋巴組織中，當受抗原感染時，具專一性之記憶性B細胞變成B細胞母細胞，進行快速增殖及分化。

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