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    Differentiation of Cd8+ T Cells Into Effector Ctls Involves

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    Mutaz Khatatbeh
    This document summarizes key concepts regarding T cell differentiation and function. It describes how CD8+ T cells differentiate into cytotoxic T lymphocytes with granules containing perforin and granzymes. Memory T cells are long-lived and respond more strongly to re-exposure to antigens. Different T helper cell subsets mediate immune responses through distinct cytokine secretion profiles and recruitment of other immune cells. The document also outlines mechanisms of T cell migration, cytotoxic killing by CD8+ T cells, and macrophage activation states.

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    Differentiation of Cd8+ T Cells Into Effector Ctls Involves

    Uploaded by

    Mutaz Khatatbeh
    60 views6 pages
    This document summarizes key concepts regarding T cell differentiation and function. It describes how CD8+ T cells differentiate into cytotoxic T lymphocytes with granules containing perforin and granzymes. Memory T cells are long-lived and respond more strongly to re-exposure to antigens. Different T helper cell subsets mediate immune responses through distinct cytokine secretion profiles and recruitment of other immune cells. The document also outlines mechanisms of T cell migration, cytotoxic killing by CD8+ T cells, and macrophage activation states.

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    This document summarizes key concepts regarding T cell differentiation and function. It describes how CD8+ T cells differentiate into cytotoxic T lymphocytes with granules containing perforin and granzymes. Memory T cells are long-lived and respond more strongly to re-exposure to antigens. Different T helper cell subsets mediate immune responses through distinct cytokine secretion profiles and recruitment of other immune cells. The document also outlines mechanisms of T cell migration, cytotoxic killing by CD8+ T cells, and macrophage activation states.

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    60 views6 pages

    Differentiation of Cd8+ T Cells Into Effector Ctls Involves

    Uploaded by

    Mutaz Khatatbeh
    This document summarizes key concepts regarding T cell differentiation and function. It describes how CD8+ T cells differentiate into cytotoxic T lymphocytes with granules containing perforin and granzymes. Memory T cells are long-lived and respond more strongly to re-exposure to antigens. Different T helper cell subsets mediate immune responses through distinct cytokine secretion profiles and recruitment of other immune cells. The document also outlines mechanisms of T cell migration, cytotoxic killing by CD8+ T cells, and macrophage activation states.

    Copyright:

    © All Rights Reserved
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    of 6

    Differentiation of CD8+ T cells into effector CTLs involves

     Development of cytoplasmic granules containing perforin & granzymes


     Secretion of cytokines, mostly IFN-γ, function to activate phagocytes
     At molecular level, 2 transcription factors: T-bet & eomesodermin are required

    Memory T cells

    1- More numerous
    2- Long lived
    3- High expression of IL-7 receptor (CD127) & CD27 (protein of unknown function)
    4- Most memory T cells express CD45RO (naive express CD45RA)
    5- Remember & respond to subsequent exposure to same Ag with enhanced ability
    6- Ability to express ↑ levels of antiapoptotic proteins (Bcl-2 & Bcl-XL)
    7- Undergo self-renewal: low-level cycling: slow proliferation (linked to stem cells)
    8- Maintenance (survival) is dependent on cytokines but independent from Ag recognition:
    a- IL-7: most imp for CD4+ & CD8+ CTLs
    b- IL-15: for CD8+ CTLs

    principles of different types of TCM-IRs

    1- TH1 cells activate macrophages.


    2- TH2 cells recruit & activate eosinophils.
    3- TH17 reactions are dominated by neutrophils (& some monocytes).
    4- Adaptive IR to phagocytosed MO which survive within phagosome is mediated by TH1
    5- Adaptive IR to helminthic parasites is mediated by TH2 cells stimulate production of IgE
    Abs & activate eosinophils & mast cells to eliminate helminths.
    6- Adaptive IR to extracellular bacteria & fungi, is mediated by TH17 cells, which recruit
    neutrophils (& some monocytes) which ingest & destroy MOs
    7- Adaptive IR to intracellular MOs, which infect, live & replicate in cytoplasm of various
    cells which are unable to destroy these MOs, is mediated by CD8+ CTLs
    8- Downregulation of IR by negative inhibitory control mechanisms (both TH1 cells &
    activated macrophages produce IL-10)  inhibit further TH1 & macrophage
    Migration of effector T lymphocytes to site of inflammation

    1- TH1 expresses
    a- Selectin ligands which bind E & P-selectin
    b- CXCR3 & CCR5 whichTH1 bind to chemokines produced by inflamed tissue
    2- TH2 expresses CCR3,4 & 8 which bind to chemokines produced by allergic and helminth-
    infected tissues
    3- TH17 expresses CCR6 which binds CCL20 produced by tissues with bacterial and fungal
    infections
    4- CTLs migrate in similar way to TH1

    Functions of TH1 cells

    1- T cells recognize microbial Ags but phagocytes actually destroy intracellular MOs.

    2- Activate macrophages
     by contact-mediated signals delivered by CD40L-CD40 binding & by IFN-γ.
     X-linked hyper-IgM syndrome:
     Inherited genetic mutations in CD40L
     Severe deficiencies in CMI to intracellular MOs (Pneumocystis jiroveci)
     Infection in children
     Defects in helper T cell-dependent Ab production

    3- Enhance microbicidal function of activated macrophages


     Classical Macrophage Activation
     To kill phagocytosed MOs in vesicles
     Mainly by actions of potent toxic substances

    Effector functions of TH2 Cells

    1- Stimulate IgE- & eosinophil-mediated IRs to eradicate helminthic Is.


    2- Activate eosinophils.
    3- Activate mast cells.
    4- Barrier immunity.
    5- Alternative macrophage activation.

    IL-4 & IL13 Actions

    1- ↑ IgE Abs:
    a- Principal mediator of immediate hypersensitivity (allergic) reactions
    b- Coat helminths & promote binding of eosinophils and mast cells
    2- Recruitment of WBCs, mainly eosinophils.
    3- Alternative Macrophage Activation (suppress IFN-γ-mediated Classical Macrophage
    Activation & inhibit host defense against phagocytosed intracellular MOs).
    4- Barrier immunity: peristalsis in GIT → expulsion of MOs ↑ mucus secretion by
    5- Differentiation & autocrine growth of TH2 cells. (only IL4 NOT IL13)

    IL-5 Actions

    1- Activates mature eosinophils


    2- Stimulates growth & differentiation of eosinophils
    3- Principal link between T cell activation & eosinophilic inflammation.
    4- Stimulates production of IgA Abs.

    Effector functions of TH 17 cells

    1- Principally induces neutrophilic inflammation by TNF & G-CSF


    2- timulates production of antimicrobial peptides (defensins) from numerous cell types.

    IL-21 Actions

    1- Important: T-dependent Ab responses: generation of follicular helper T cells &


    stimulation of B cells in germinal centers.
    2- Autocrine differentiation of TH17 cells.
    3- Proliferation & effector function of CD8+ T cells & NK cells.

    Effector functions of differentiated CD8+ CTLs

    1- Eradicate intracellular MOs in


    a- Non-phagocytic cells which lack intrinsic microbicidal ability
    b- Phagocytic cells; as phagocytosed MOs escape from phagosomes

    2- Defects in development & activity of CTLs → ↑ viral & some bacterial infections and
    reactivation of latent virus infections (EBV)

    Steps of CTL-mediated cytotoxicity

    1- Specific Ag recognition.
    2- Activation of CTLs.
    3- Killing/ death of target cells is a result of apoptosis.
    4- Release of CTLs.
    In addition to TCR, CTLs express other receptors

    1- Killer Ig receptors (KIR)


    - recognize class I MHC molecules on target cells
    - NOT specific for particular peptide-MHC complex
    - transduce INHIBITORY signals

    2- NKG2D receptors
    - Recognize class I MHC-like (MIC-A, MIC-B & ULBP) on infected or neoplastic cells.
    - May deliver signals to enhance killing ACTIVITY.

    There are 2 main CTL-mediated killing mechanisms of target cells:

    a- Principal mechanism: Granule-dependent mechanism Granule exocytosis process


    1- Perforin (homologous to C9): form pores in target cell membrane
    2- Granzymes (serine proteases, include caspases) cleave proteins & initiate apoptosis
    3- Serglycin (sulfated proteoglycan) assemble perforin & granzymes
    4- Granulysin: alter permeability of target cell & microbial membranes

    b- Granule-independent mechanism: Fas/TNF-mediated killing


    - Ligand: FasL : on surface of activated CTLs which binds  Receptor: Fas; death receptor
    expressed on surface of many target cell type
    - CTLs also secrete TNF-α w binds TNF death receptor on target cells
    - Binding: → activation of caspases → death of Fas-expressing target cells by apoptosis

    CTLs themselves are NOT injured during killing of Ag-expressing target cells because of:

    1- Directed granule exocytosis process is highly specific


    2- Cathepsin B: degrades errant perforin molecules which come into vicinity of CTL

    NKT & T cells with γδ TCR (γδ T cells)

    - Smaller populations of T cells


    - Recognize wide variety of Ags without processing or MHC molecules
     peptides
     lipids (NKT cells)
     small molecules (γδ cells)
    - MHC-independent, Not MHC-restricted
    - Abundant in epithelial tissues, as GIT
    NKT cells

    - Express CD56 & Recognize lipids & glycolipids Ags displayed by CD1 protein molecules
    - CD1
     Non-MHC encoded & non-polymorphic
     “Non-classical” class I MHC-like
     Structurally homologus to class I MHC alpha chain
    - Protective innate IR against some bacteria as mycobacteria with lipid-rich cell walls.

    γδ T cells

    - <5% of all T cells vs. more numerous T cells with αβ TCR.


    - Recognize small phosphorylated molecules & alkyl amines.

    Macrophage activation Classical (pro-inflammatory) Alternative (anti-


    inflammatory)
    Enhanced by TH1 TH2
    Inducing stimuli Microbial products (LPS) IL-4 & IL-13
    IFN gamma
    Characterized by secreting IFN gamma IL-10 & TGF β that inhibit TH1
    Host defense Microbicidal activity Tissue remodeling
    ROS, NO Tissue repair
    Lysosomal enzymes Fibrosis
    Cross presentation (cross printing)

    - Violation of the conventional pathways for Ag presentation


    - Transport of some epitopes in the phagosome into the cytosol
    - Cytosolic epitopes are presented by MHC I for cytotoxic lymphocytes
    - Phagosomal epitopes may presented by MHC II for T helper cells (not necessary but
    required sometimes for full activation of CD8+)
    - Used when
     Virally infected cell or tumor cell can’t present the Ag
     The whole cell will be captured and ingested by DCs
    - One cell type (DC) can present Ag from another cell (virally infected / tumor cell)
    Miscellaneous

    - Tears contain lysozymes that can damage bacterial cell wall (1st line defense)
    - Periodic flow of urine and stool defecation are considered to be 1st line defenses
    - Corneal transplantation has the highest success rate with no rejection (avascular)
    - Ficolin: circulating lectin, binds mannose on microbial surface & activates complement
    - Effector functions of Abs are initiated only by Ag-bound Abs (not free forms)
    - For the antibody to perform the effector functions it must
     Be in the secreted form (not membrane-bound)
     Bind the antigen (Ag-bound not free, 2 or more Fc regions are required)

    - HLA DM
     MHC-encoded
     Similar to structure of class II MHC
     Not polymorphic
     Not expressed on cell surface
     Acts as peptide exchanger
     Facilitates removal of clip from peptide-binding cleft of MHC II
     Accelerates addition of peptides to class II MHC

    - Valency of Ab
     Number of Fab regions
     Four in IgA dimer
     Ten in IgM pentamer

    - Serum is plasma devoid of the coagulation factors (plasma – clotting factors)


    - Serum proteins can be separated by electrophoresis process

    - Rintatolimod (Ampligen)
     Structure: ds-RNA
     Binds to TLR-3
     Used to treat chronic fatigue syndrome (CFS)

    - Chediak Higashi syndrome


     Rare autosomal recessive disorder
     Characterized by recurrent infection
     Associated with oculocutaneous albinism
     Giant lysosomes form in neutrophils during the maturation
     Etiology: mutation in LYST gene (responsible for lysosomal trafficking)
     Defective lysosome-phagosome fusion in neutrophils and macrophages
     Impaired function of NK cells due to abnormality in the cytoplasmic granules

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