Lymphocyte Development Lecture PDF

Lymphocyte Development B cell development Janeway’s Immunobiology, 9th edition  Lymphocytes derive from hematopoietic stem cells in the bone marrow pluripotent : give rise to multiple lineages of cell Lymphopoiesis is the production of new lymphocytes. Lymphopoiesis takes place in...

Lymphocyte Development B cell development Janeway’s Immunobiology, 9th edition  Lymphocytes derive from hematopoietic stem cells in the bone marrow pluripotent : give rise to multiple lineages of cell Lymphopoiesis is the production of new lymphocytes. Lymphopoiesis takes place in the central (or primary) lymphoid tissue – bone marrow for B cells, and thymus for T cells. New lymphocytes migrate to the peripheral (or secondary) lymphoid tissues – spleen, lymph nodes, mucosal lymphoid tissues – where immune responses occur. Mature in the mymus In the bone marrow, hematopoietic stem cells (HSC) first to make + cells. differentiate into multipotent progenitor cells (MPP), which a can produce both myeloid and lymphoid cells but are no CMP/CHP point At some HST from MPP : differentiate In longer self-renewing stem cells. ↳ giving lymphoid either rise to Myleod sell type All lymphocytes are derived from a common lymphoid progenitor cells (CLP). Three subsets of CLP cells arise from MPP: - A subset with broadest potential to generate B cells, T cells and NK cells. - A subset able to generate only B cells and T cells. - B cell-committed subset gives rise to B cells only. > cytokines - that mediate different of Cup to become lymphold cell + produce lymphocyte FLT3 ligand and IL-7 produced by the bone marrow stromal cells are essential for production of CLP form MPP.  development completed in multiple B cells develop in the bone marrow staged ↳ have different signals growth , factor each stage produced by stromal cell ↓ develop into B cells through signal cells to diffrentiate + become a 13 cell Factors essential for B cell development in the bone marrow: (growth) -IL-7 is essential for growth and survival of developing B cells in mice. stimulate growth By binding tyrosine to Kinase 14 + -Stem cell factor (SCF) – a membrane-bound proteins present on bone marrow stromal (growth) cells, interact with receptor tyrosine kinase Kit on developing B cells to stimulate growth. - Cell adhesion molecules (CAM) and chemokine CXCL12 (stromal cell-derived factor 1, developing & SDF1) (retain) are required for retaining developing B cells in the bone marrow. B cells have - Thymic Cnymr to be in contact produced by can be discovered other cell also , but has ws stromal sell stroma-derived lymphopoietin (TSLP) – resembles IL-7. I In the thymus y specific developingfor B cells through cell expression adnelson molecule - Transcription factors – E2A (B-lineage specific), early B cell factor (EBF), Pax5/BSAP. reguiale ↳ gene importantof for development of B-cells  B cell receptor gene rearrangement at different receptor stages of B cell development prese e · If B-cell has noreceptor - then no function - early - · expression of receptor on surface of cell makes Sure B-cells produced has receptor > rearrangement occurs during development - Of B-Cell > - rearrangement of VD] I chain before ELA/EBF rearrangement of VI chain. rearrangement of H chair · I chain recombination - early proB cell stage (VDJ) ↳ completed at end of early pro-B cell Stage · It unable to form H-chain then B-cells , can't communicate to next stage. Induces 11-7 to & promove proliferate · large pre-B cell stage : where cell cheers validity of # enain > - · HaDeexpresa + can be expressed - ·Achan development expressed (invariant (chains induce It chain rearrangement wa Immature B-cell ↑ eleased from BM - signal rent to ensure proper rearrangement 00 E2A and EBF transcription factors induce expression of recombinase components to initiate H-chain that can be expressed on pre cell surface produced expresses 19 Molecules pre cell stage leda expressed in > from chain > - &- - , rearrangement in early pro-B cells. doesn't have same variable domain replace (chain of 19 > - - > expressed suraeeeling on > forms fully functional receptor - of Bell : ⑳O + Rearranged H-chain pairs with two invariant surrogate L-chains, λ5 and Vpre B, to form pre-B receptor. a set interacts W ↳ bloat preparessignal trans... pre B receptor vpreB 15+ preBreceptor = Signals through pre-B cell receptor and its signaling components (Igα, Igβ, etc.) ensure proper gene developing nave a copies of -ca genome 12H , 21) cell rearrangement and transition between pro-B and pre-B stages. , /i allele produced starts recombination , once right L/H recombining chain it stop the other allele Pre-B receptor signaling halts further H-chain gene rearrangement, enforces allelic exclusion (only one of the two alleles of a gene is expressed), and increases sensitivity to IL-7 to induce cell proliferation. (small) L-chain gene rearrangement is initiated in the pre-B cell stage to form a fully function B cell receptors protien forming IgM -chain pair w/H-chain and further maturation of B cells. ↳ bound to cell surface act as i cell receptor  Gene rearrangement and expression of pre-B and B cell receptors Formation of pre-B cell receptor and signaling provide an important checkpoint that mediates the transition between the pro-B and the pre-B cell. ↳ recomb. of VDJ begins is Importanfor recen , > - recomp vJ then UDJ to form recombined It chain gene > MRNA > splicing - produces H-chain - - make sure Its functional. Pro-B cells that do not produce a- µ chain are for IgM. It chain undergoes testing to eliminated as they fail to receive important survival signals mediated by the pre-B receptor. H-chain locus can undergo successive.H 2 chain paired up wi invariant chain rearrangement in the same allele followed by the 3. From 19 light Molecule on B cell surface second allele until cell death or successful pre-B ↳ > - can bind to singal receptor signals halt further rearrangement. + invariant to B-cells chain u cells divide proliferate &. change into small pre B cell stage L-chain gene rearrangement initiates following > - This initiate recomp Of gene for ( chain.. several rounds or cell division upon successful pre- ↑ B receptor signaling. again try cell is allowed to to produce proper chain. light chain forms receptor immature B-cells tested against selfAgo. L-chain gene also undergoes successive VJ ↳ If falled then go back rearrangement on the same allele followed by the + produced another ( chain. second allele if initial rearrangement fails. cell dies If can't compete S recombination If produced good chain then undergoes alietic L-chain rearrangement also exhibit allelic (H-chain) + Isotypic exclusion. exclusion, as well as, isotypic exclusion, i.e. expression of only one type of light chain – κ or λ – producing when a good It gene chain then specificity of by an individual B cell. Is located Only - undergo gene recomp Will one allele of thathas expression - Allelic undergone. exclusion  Immature B cells are tested for autoreactivity before they leave the bone marrow ↳ any immune cell that can react strongly against self Ags. - can cause autoimmune disease : have to be checked it receptors Four possible fates for self-reactive immature B cells: doesn'Dind self Ag. * If don't bind then they can leave Done marrow - Receptor editing – production of new receptors. - Apoptosis – clonal deletion only * doesn't one that to periphery move * - Anergy – a permanent state of unresponsiveness to antigens. - Immunological ignorance – can be activated under certain conditions such as inflammation or high concentrations of the self-antigen. It react to solvable Ag then , undergo dllergic (unresponsives turn off cunactivated) + die in I some can build/react to self ag but wearly : Won't activate : can't exit the bone marrow ↳ can get activates in some situations lex. Infection  Some autoreactive B cell undergo peripheral tolerance ↳ sometimes exit Done marrow enter + periphery > has - Mechanism that can check B. cells There is no receptor edition once a B cell leaves the bone marrow. B cells that encounter their autoantigen for the first time in the periphery are eliminated or inactivated while they are still not fully mature – peripheral tolerance. any Immature B cells leave BM (only Interact / Final maturation and long-term survival of B cells in the spleen IgM) + enter spleen (matures B-cells mature in follicles Two distinct transitional stages of B cells (T1 and T2) in the spleen are defined by the expression of CD21 (complement receptor 2). The TNF-family member BAFF is a B cell survival factor produced by the follicular dendritic cells (FDC). produce bused progress > BAFF in of T1/T2 Signaling through the BCR and BAFF receptor are required for B cells when leave follicles enter iz stade to progress through the T1 and T2 stages. & The majority of peripheral B cells in the secondary lymphoid organs lymphold organs (Found in 20 are known as follicular B cells (a.k.a B-2 B cells) because the reside lymphold 2 (B Bell B cells are Follicular B cells 2 in the follicles.. (Found in spleen A minor population of B cells in the spleen consists of marginal zone B cells. Fully mature B cells express high levels of IgD and low levels of IgM, as well as, CD21 and chemokine receptor CXCR5. B-1 B cells are an innate lymphocyte subset that arises early in development · bind to only Ag that affect vs able to divide + renew in body ↑ · Innate counterparts of B. Cell · produced during embryo stage As part of the innate immune system, B-1 B cells are found in large numbers in the peritoneum and pleural cavities. Majority of B1 B cells develop from progenitor cells found in the fetal liver during the late fetal and early neonatal stages. Few B1 B cells are produced after specificity receptor have less as birth. naturallypresent body in , prod as B1 B cells are the major source of natural antibodies – constitutively produced circulating antibodies – against carponydrate Ag > must abs are specific (in cell wall) without T cell help. Natural antibodies are produced spontaneously, have restricted V-region diversity, and mostly respond to carbohydrate antigens.  T cell develop in the thymus ↳ have same CLP B Cell by - ↳ CLP leave bone marrow into thymus for +-cells ↳ Notch receptors interact w , > If progenitor sels don't express CDO/CDY T cell progenitors originate in the bone marrow and migrate to the thymus to develop into mature T cells. In the thymus, progenitor cells receive signals from thymic epithelial cells through Notch1 receptor to commit to T cell lineage. Developing T cells in the thymus are called thymocytes. ~undergodevelopment s directly development Both the αβ TCR and γδ TCR T cells arise from the same (Minor > It express both y + 8 Subsel) progenitor cells. helper Cytotoxic αβ T cells (CD4+ and CD8+ T cells) develop through double negative (DN), double positive (DP) and single positive (SP) stages in the thymus. as become more mature they become either CDY/CD3 Only 2-4% of thymocytes develop into mature T cells. The die dining It can't make development proper thymocyte (single +) rest die in the thymus by apoptosis which are ingested and receptor ↳ then become cleared by macrophages. inymus removal of mature tre MEC-TOMY] ↑ [THY- Surgical removal of the thymus in mice (thymectomy) and DiGeorge syndrome in humans and mice, where the thymus fails to develop, results in T cell deficiency. ↳ can be serve - immunodeficient ↳ mulation can carse fallure of thymus development: no T-cells arrangement of t-cell gene Stages of α:β T cell development in the mouse thymus can be divided dont express ODU/CD2 developing develop either CDY or CDE need proper receptor Into 1 stades x ↑ T all express ↑ double negative : & chain & chain have own gene : rearrange rearrangement CD > expressed CDU + CD3 produce proper receptor die - + ↳ Unable to receptor of variable ofX chain 1 recombination of VD] in double T-cell segment CDS > - rearrangement VD] region gene start of B cell receptor express receptor on cell surface negative stage > - recognize self MHC Ag 2 variable region , Pia pair up W/ B-cells + form. Ag specificity tested rangement > - PTCR > Interacts W/ Ag through neon le sona - 4 MHC molecule ↓ :: have to recognize It self Ag activities them then they MHC receptors , self Ags are auto reactive can undergo multiple rearrangement of : undergo recombination again Bchain. ↓st Stage : MHC recognition lesled to make sure * stop expression of and allele once they recognize self MHC molecule expressed 1st allele * * only selects +cell that can develop in nemopoetic stem sells recognize self MHC (MHC restrict 2nd stade : check ag specificity It recognition , self Ag + activate they die through process called (negative selection) : keeping T-cells that recognize self MHC molecule wo reactive against self Ag ↳ Only 2 9 % - of toid / thymocyte present. contains vs combination followed by UDJ ( ?) - alls make sure that rearrangement occurs The DN stage is subdivided into 4 stages (DN1-4) on the basis of CD44 (adhesion molecule) and CD25 (IL-2 receptor). Rearrangement of TCR β-chain locus begins in DN2 thymocytes. pret-cell pret receptor receptor make cell -parw/beta and assmouy / In DN3 thymocytes, expressed β-chain stage pairs with a surrogate ① pTα chain and O CD3 to form pre-T cell allow cell to move to the next of development receptor (pTCR). pTCR signals arrest β-chain gene rearrangement, and induces cell proliferation and rearrangement (DNU) rid of self-reactive cells before & chain differentiation to DP thymocytes. get Bendin Double-positive chain - crearrange & chain , vs chain The α-chain gene rearrangement begins in the DP thymocyte which constitute majority of thymocytes. forward then won't more 11 then can more forward If not recognize they recognize - , The α locus allows successive attempts at rearrangement to generate a productive CD3:αβ TCR complex. DP thymocytes undergo positive and negative selection to select thymocytes which recognize self peptide:self MHC complexes and eliminate those which respond to self antigens, respectively. About 2% of DP thymocytes survive the selection process to form both CD4+ and CD8+ SP thymocytes. ↓ due to the previous slides The stages of gene rearrangement in α:β T cells (1) & during double negative stage V DJ recombination recombination w/ variable region The stages of gene rearrangement in α:β T cells (2) express PTCR ↓ once allele is functional , & then It will lock and rearrange + this is the sequence that (now functional pid chan will transcribe signalling component, It it can recodmic self MHC then are functional If they don't you can , go back and rearrange to be successful. * they are given the chance to rearrange again it they do not function Fall to form , those cells will die & Majority of the cells will die here rearrange vs to make a chain to make-  Thymocytes at different developmental stages are found in distinct parts of the thymus positive > single - Most T cell development takes place in the cortex; only mature O SP thymocytes are seen in the medulla. Assist In Positiveselection can express MHC 1 and MHC I * CORTEXA & - The cortical stroma is composed of epithelial cells which express both class I and class II MHC. MHC interaction with developing T cell receptor has a crucial role in positive selection. * MEDULLA * assist in negative selection & Medullary epithelial cells and dendritic cells play a role in negative selection in the medulla. I rearrange to make R and haveThe nat can recognize 2 + 16sVe 1. corlex (immature 2. medullary mature they will more down I here tomanurea Into CDY or CDE  Positive selection of thymocytes have rearrange a /B , T cellreceptor that can recognize self MHC Molecule can't recognize antigens presented on them DP thymocytes Double positive (DP) thymocytes express low levels of TCR and both the CD4 and CD8 co-receptors. Only 10-30% of DP thymocytes express TCR capable of recognizing self-peptide:self-MHC complex and are rescued from Crescued death) from cell programmed cell death – positive selection. to mediate Interact N/ Thymocyte T cell receptor and CD3/y must interact With self MAC > - Signals Thymic cortical epithelial cells express both class I and class II MHC molecules and mediate positive selection. Binding of both the TCR and the co-receptor (CD4 or CD8) by an MHC molecule is required for positive selection. Positive selection through TCR-MHC interactions also determine DP thymocytes co-receptor specificity; DP thymocytes selected by MHC class I develop into CD8+ thymocytes, while those selected by MHC class II develop into CD4+ thymocytes. receptor recognize MHC 11 then develop Into CD4 + If I tell W "MHC 1 then develop into CDST  Negative selection of thymocytes contain +ve thymocyle specific NOT tested - antigen Developing thymocytes which react strongly to self-antigens die by cinduce death) cell apoptosis – negative selection. ↳ testing their antigen specificity Negative selection can occur both in the thymic cortex and medulla at DP or SP thymocyte stage. they they peptide contain self activate , induce programmed death selt Negative selection is mediated by immative G cortical epithelial cells, medullary epithelial cells and bone marrow- derived antigen presenting cells mediate ve selection development - mature cells will continue (APC). only Bone marrow-derived APC (DC and macrophages) are most efficient at mediating negative selection in the thymus. Negative selection in the thymus may not remove all of the self- reactive thymocytes, however, several mechanisms operating in the periphery can prevent mature T cells from responding to self- antigens.  The final stage of T-cell maturation (leave ine inymus Final stage of T cell maturation occurs in the thymic medulla. lipid nigh , In circulation + conc Mature T cells express S1PR1 receptor for and lymph sphingosine 1-phosphate (S1P) present in high sense conc. gradient out of thymus into concentration in the blood and lymph, which the circulation draws T cells out of the thymus. must remain In Go issue lymphold >movecent se - T Mature T cells also express CD62L (L-selectin), a these I Cell lymph node homing receptor that facilitates naïve undergo can peripheral T cell localization to peripheral lymphoid organs. toeramen Auto-reactive T cells which make it to the periphery are either eliminated after a brief period of activation and cell division (activation-induced cell death) or rendered anergic. mechanism that prevent self... chance that cells are autoreactive ~ can undergo unresponsive to antigen  * developed during embroyonc slage γδ T cell development (minors develop independently develop > not antigen - in thymus Specific same process as /3 do not welego the this occros in the thymus in waves appear * don't need to remember each type e ach of the wave , reside at atomical The epititial cell Most reside with the intestinal tract. atter birth reside in the atter birth minimal very > - γδ T cell subsets arise in distinct phases during development. nembryondevelopme a -occur In mice, the majority ofO γδ T cells in the body arise during embryonic development and the early neonatal period.