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SEL-T, Sel- B dan MHC

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SEL-T, Sel- B dan MHC. Dosen Imunologi Fakultas Farmasi Universitas Pancasila Jakarta. Produksi sel darah dan leukosit. Cell-Mediated Immunity. Adalah respon adaptiv imuniti yg di mediasi oleh sel sistem imun spesifik: - PowerPoint PPT Presentation
  • SEL-T, Sel- B dan MHCDosen ImunologiFakultas Farmasi Universitas PancasilaJakarta

  • Produksi sel darah dan leukosit

  • Cell-Mediated ImmunityAdalah respon adaptiv imuniti yg di mediasi oleh sel sistem imun spesifik:lymphocytes T Primer (T cells), juga sel macrophages dan sel NK .Adalah immunitas yg dapat ditransfer dr satu organisme ke organisme lain oleh sel limfoid, tetapi tdk dengan antibodi serum.

    Sel-T adalah agen utama dari selular imuniti.y

  • Sel-T Adalah koordinator utama dan effektor dari komponen selular imuniti

    Terciri oleh perkembangannya di dalam Thymus dan adanya T-cell receptor (TCR) complexCD8+ cytotoxic T cell killing a tumor cell

  • Sel-TAda dua tipe utama:1. CD4+: Stimulate other immune cells.2. CD8+ Cytotoxic T cells: Kill intracellularly-infected cells.Ada dua tipe utama dari CD4+ T cells:1. TH1: Inflammatory T cells -- Stimulate macrophages and promote inflammatory responses. 2. TH2: Helper T cells -- Stimulate B-cells to produce antibodies.(A third type, TH3, has recently been shown to promote IgA production.)

  • Perkambangan sel-T dalam ThymusCortexMedullaImmature double-negative T cells (CD8-, CD4-)Immature double-positiveT cells (CD8+, CD4+) Positive selection/negativeselectionCD8+ T cells CD4+ T cellsMature T cells

  • Reseptor sel TSimilar in structure to Immunoglobulins (similar to a single Fab fragment.Composed of two glycoprotein chains (/ or /). Most mature T cells have TCRs composed of an chain and a chain (they are called / T cells).Each chain has a constant region and a variable region, similar to an antibody light chain.A TCR recognizes a small(8-13 aa) peptide epitopedisplayed on MHC

  • TCR compared to ImmunoglobulinsSimilaritiesBoth have specific Antigen-binding region created by the variable regions of two polypeptide chains.Both display great potential for diversity via genetic recombination at the genome levelDifferencesA TCR is monovalent (has one binding site). An Ig is bivalent (has two binding sites).The TCR has no secreted form. It is always membrane-bound.The TCR does not recognize free antigen. Antigen must be presented to a T cell on an MHC molecule There is no class switching for the TCR. Once made, the TCR does not change. chain chainEpitope-binding siteVariable regionConstant regionTransmembrane regionT cell ReceptorImmunoglobulin

  • The T cell Receptor, cont.The TCR only recognizes specific peptide/MHC complexes expressed on the surfaces of cellsA TCR complex is composed of one heterodimeric TCR (ususally /), plus a 5-polypeptide CD3 complex which is involved in cell signalling for T cell activation.Each TCR is produced through genetic recombination and recognizes one small peptide epitope (about 8-13 amino acids). One T cell expresses only one specific type of TCR.

    CD3 is the activation complex for the TCRBinding of antigen/MHC to the TCRstimulates CD3. CD3 then sends an activation signal to the inside of theT cell.

  • TCR genetics: Similar to Ig genetics(numbers of segments in book is off, just like for Ig genes) chain chain

  • Responses to infection -- T cell componentInfectionInfectionInfectionInfectionInfectionInnate immunity(0-4 hours)Early inducedresponse(4-96 hours)Late adaptiveresponse>96 hours)Protective immunityImmunologicalmemoryRecognition bypre-formed, non-specific effectorsRecruitment ofeffector cellsTransport ofantigen tolymphoid organsRecognition bypre-formed, Aband T cellsRecognition bymemory B cellsand T cellsRemoval ofinfectious agentRemoval ofinfectious agentRemoval ofinfectious agentRemoval ofinfectious agentRemoval ofinfectious agentRecognition andactivation ofeffector cellsRecognition by naveB and T cellsClonal expansionand differentiationto effector cellsRapid expansionand differentiationto effector cellsThe adaptive immune response involving antigen-specific T cells and B cells is only one part of the immune response and is required to protect against pathogens. A pathogen is by definition an organism that can cause disease. In other words, a pathogen is an organism that can bypass innate immunity and requires an adaptive immune response for clearance.

  • Generation of an adaptive immune responseDuring an adaptive immune response,T cells which recognize specific antigen(s) are selected for differentiation into armed effector cells which undergo clonal expansion to produce a battery of antigen-specific cells.Clonal expansion refers to the process by which antigen-specific T cells or B cells are stimulated to reproduce clones of themselves to increase the systems repertoire of antigen-specific effectors.Activation of antigen-specific T cells (the initiation of the adaptive response) occurs in the secondary lymph tissues (lymph nodes and spleen). This activation depends upon antigen presentation by a professional antigen presenting cell (APC) along with simultaneous co-stimulation. (eg., B7 on the APC, CD28 on the T cell).

  • Initiation of the adaptive immune responseThe first step is the draining of antigen into the lymph node(s).In the lymph node(s) (or spleen), antigens are trapped by professional APCs which display them to T cells.

  • The professional Antigen Presenting Cells (APCs)Three types of APC are found in the lymph nodes:Dendritic cells -- constitutively express MHC I and MHC II (can stimulate both CD4+ and CD8+ T cells) as well as B7 (the co-stimulatory signal). Antigen presentation appears to be the sole purpose of dendritic cells, and these cells can be infected by a wide variety of viruses. Dendritic cells are not phagocytic. They can present some viral peptides on their MHC II, and contribute to the induction of antibody against viruses. They are very efficient at stimulation of cytotoxic responses.Macrophages -- Resting macrophages express little MHC II or B7, but have receptors for bacterial cell wall components which, upon binding, activate the macrophage to express high levels of B7 and MHC II. Once activated, macrophages are efficient at stimulating CD4+ T cells, both for inflammatory responses and helper (antibody) responses. B cells -- B cells express high levels of MHC II, but not B7. Microbial cell wall components can induce B7 expression by B cells (like macrophages). Once induced to express B7, B cells can activate helper T cells. B cells can take up soluble antigen through their Ig receptors (unlike dendritic cells or macrophages).

  • The antigen presenting cells, continuedDendritic CellMacrophageB cellNote: this B cell is not a plasma cell -- a plasma cell is shown above. Plasma cells do not present antigen. They simply pump out antibody for a few days then die.

  • Capture of circulating T cells in lymph nodes

  • T cells continuously circulate via the blood and lymph through different lymph nodes until they either find presented antigen or eventually die When a T cell encounters an APC displaying antigen to which it can bind, it stops migrating and binds strongly to the APC.Within about 2 days (48 hours), most antigen-specific T cells have been trapped by antigen and within about 4 to5 days armed effector T cells are migratingout of the lymph node.

  • Review -- Cytokines produced early in response to infection influence the future functions of activated CD4+ cellsCytokines produced by TH1 cells inhibit TH2 cellsCytokines produced by TH2 cells inhibit TH1 cellsAn immune response is often dominated by a cell-mediated response or an antibody response.Some pathogens have evolved strategies to shift the immune response toward the less effective type for that pathogen.

  • Functions of the different T cell typesCD8+ cells: Kill virally infected cellsCD4+ cells: TH1: Activate macrophages to aggressively ingest antigen and to kill ingested microbes.TH2: Stimulate B cells to differentiate into antibody-producing plasma cells. B cells will only undergo isotype switching after receiving T cell help. The Ig class that a B cell switches to is specified by the types and balance of cytokines secreted by the helper T cell. Most plasma cells migrate to the bone marrow where they live out the rest of their lives.

  • One cytotoxic T cell can kill multiple targetsA cytotoxic T cell causes its target to undergo apoptosis (cell suicide) by the focussed secretion of vesicles carrying cytotoxins.The T cell binds to its target, delivers its cytotoxins, and moves on before it has a chance to be hurt itself (one T cell can kill another, so a T cell is not immune to the cytotoxins). Micrographs:Left: healthy cell.Middle: lower right cell is in beginning stage of apoptosisRight: small cell in middle is in advanced apoptosis. Its nucleus is highly condensed and it has shed much of its cytoplasm.

  • Immunological memoryWhen B cells are activated to reproduce, some differentiate into plasma cells and some become long-term memory cells. An adaptive immune response also produces T cell memory, but the nature of memory T cells is unknown. Two possibilities exist. Memory T cells probably originate from either:1. A long-lived subset of effector T cells that differentiates into memory T cells -- like memory B cells.2. The continuous low-level activation of nave T cells by specific antigen that is retained in the lymph nodes after an infection. This mechanism would suggest that APCs in the lymph node hold on to antigen on a long-term basis after an infection and continuously stimulate T cells at a low level so there is always a small effector population ready to go.

  • MHC classes I and IIFunctions:class I MHC: Displays peptides derived from antigen originating inside the cell (endogenous antigen).Important in cytotoxic responses (eg, CD8+-killing of virus-infected cells).Class II MHC:Displays antige

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