Development of B and T lymphocytes

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1 Development of B and T lymphocytes

2 What will we discuss today? B-cell development T-cell development

3 B- cell development overview Stem cell In periphery Pro-B cell Pre-B cell Immature B cell Mature B cell Memory B cell In bone marrow Plasma cell Modified from Immunology for medical students, 2 nd edition

4 B- cell development Stem cells - in fetal liver - in bone marrow soon after birth In bone marrow radial maturation pathway B lineage cells develop into immature B cells with membrane-bound IgM molecules these will leave the bone marrow These will acquire the ability to recirculate and populate all peripheral lymphoid organs Further maturation primarily in the spleen into follicular B cells expressing IgM & IgD on their surface

5 B- cell development, cont d From lymphoid progenitor to mature B cells: 2-3 days The earliest committed B-lineage cell is pro-b cell Characterized by appearance of B lineage surface markers, e.g., CD19 -RAG proteins are first expressed at this stage -DJ & V to DJ recombination then occurs, and mu heavy chain is produced -TdT is most abundantly expressed here

6 B- cell development, cont d

7 B- cell development, cont d Rearrangements at IgH locus must be productive 1/3 of pro-b cells now Ig mu heavy chain can be formed now the cell become: pre-b cell In early pre-b stage: two polypeptides associate non-covalently to form the surrogate light chain, and pair with the heavy chain -delta 5 -VpreB

8 B- cell development, cont d Surrogate light chains are invariant Mu + surrogate light chains + Ig alpha + Ig beta = pre-b cell receptor Bruton s tyrosine kinase (BTK gene) is activated downstream Its signaling is responsible for B lineage expansion (survival, proliferation and maturation) Its mutation will cause:.

9 B- cell development, cont d Pre-B cell receptor also inhibits rearrangement of heavy chain locus on the other chromosome If the rearrangement was non-productive, the other allele can compensate Pre-B cell receptor also inactivate surrogate light chain gene expression Rearrangement of kappa or lambda which associates with mu here the cell becomes immature B cell

10 B- cell development, cont d Kappa is rearranged after heavy chain and before delta rearrangement of kappa inhibits delta rearrangement 2 conditions in which delta will undergo recombination??? Allelic exclusion also applies for light chain Immature B cell will exit the bone marrow and complete maturation in spleen otherwise they -undergo receptor editing = clonal deletion -die -or become unresponsive = anergy By reactivation of Rag genes and new recombination of light chains (Negative selection)

11 B- cell development, cont d Mature naive B cells will die in a few months if they do not encounter antigens and recognize them with high affinity (respond to antigens) For mature B cells expressing IgM & IgD: binding with high affinity leads to proliferation & differentiation leads to humoral immune responses B-1 and marginal zone B lymphocytes?????

12 T- cell development overview Double-negative (CD4- & CD8-) in subcapsular zone Selection of DP cells by MHC class I or class II molecules in cortex Positive selection if recognize self MHC and negative selection if recognize self MHC with self-peptide antigens Commitment to alpha beta or gamma delta lineage Selection of single-positive cells depending on the MHC molecule.in medulla So those that are selftolerant and selfrestricted are retained = lineage commitment Double-positive cells in cortex Release of naive mature T cells

13 T- cell development Congenital absence of thymus will cause immunodeficiency Thymus involutes with age but memory T cells have long life span Precursors from fetal liver and adult bone marrow will seed the thymus thymocytes

14 The TCR Ch. 14 Ch. 7 2 lineages 95% alpha beta within the remainder gamma delta Ch. 7 *Beta & delta: VDJ *Alpha & gamma: VJ transmembrane Accessory molecules for TCR: -CD3 (4 transmembrane protein chains gamma, delta, epsilon and zeta) -LFA-1 (= CD11a) an integrin *A tyrosine kinase (Lck of Src family) is brought into proximity of CD3 cytoplasmic part by CD4/CD8

15 T- cell development, cont d The most immature thymocytes: negative for TCR, CD4 or CD8 In subcapsular sinus and outer cortex In cortex: expression of gamma delta and alpha beta TCRs see next slide Alpha beta T cells begin to mature into CD4+ class II MHC-restricted or CD8+ class I MHC-restricted T cells see slide 17 Then to the medulla then to the circulation Role of other cells in thymus (expressing MHC & secreting cytokines) (+) for CD44 & CD25 (alpha chain of IL-2 receptor)

16 T- cell development, cont d Cortical thymocytes proliferation and apoptotic activity 95% before reaching the medulla Sensitive to irradiation and steroids Rearrangement of beta, gamma, and delta -at DN stage -if functional gamma delta receptor produced gamma delta TCR-expressing T cell results -if TCR beta chain with invariant pre-t alpha chain and CD3: = pre-tcr complex signal transduction: stimulation of proliferation, halting beta rearrangement and promoting alpha rearrangement

17 T- cell development, cont d Positive selection of DP thymocyte with help of cortical epithelial cells Self-MHC restricted cells are produced these need to be self-tolerant otherwise?? With help of dendritic cells in medulla

18 Autoimmune regulator gene (AIRE) Regulate expression of antigens of endocrine cells in thymic epithelial and non-epithelial cells Mutation autosomal recessive disease autoimmune polyendocrine syndrome I (APS-I)

19

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