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Kindt • Goldsby • Osborne Kuby IMMUNOLOGY Sixth Edition Chapter 14 Cell-Mediated Cytotoxic Responses 宜蘭大學 動物科技系 免疫學 王愈善 1 Copyright © 2007 by W. H. Freeman and Company Outline 2 Effector Responses General Properties of Effector T Cells Cytotoxic T Cells Natural Killer Cells NKT cells Antibody-Dependent Cell-Mediated Cytotoxicity Experimental Assessment of Cell-Mediated Cytotoxicity Outline 3 Effector Responses General Properties of Effector T Cells Cytotoxic T Cells Natural Killer Cells NKT cells Antibody-Dependent Cell-Mediated Cytotoxicity Experimental Assessment of Cell-Mediated Cytotoxicity Effector Responses The principal role of cell-mediated immunity is to detect and eliminate cells that harbor intracellular pathogens. Cell-mediated immune responses can be divided into two major categories A. direct cytotoxic activity B. effector CD4+ T cells that mediates delayed type hypersensitivity reactions 4 p.352, left column Outline 5 Effector Responses General Properties of Effector T Cells Cytotoxic T Cells Natural Killer Cells NKT cells Antibody-Dependent Cell-Mediated Cytotoxicity Experimental Assessment of Cell-Mediated Cytotoxicity 6 7 Outline 8 Effector Responses General Properties of Effector T Cells Cytotoxic T Cells Natural Killer Cells NKT cells Antibody-Dependent Cell-Mediated Cytotoxicity Experimental Assessment of Cell-Mediated Cytotoxicity Generation of effector CTLs 1 3 2 9 Proliferation of memory CTL-Ps may not require help from T H cells. 10 MHC tetramers A given MHC-tetramer– peptide complex binds only CD8+ T cells that have TCRs specific for the particular peptide-MHC complex. p.355, left column 11 Localizing antigen specific CD8+ T-cell populations in vivo 12 Scanning electron micrograph of tumor-cell attack by a CTL CTL Tumor cell 13 Stages in CTL-mediated killing of target cells TCR-CD3/MHC I LFA-1/ICAMs 14 Antigen-mediated CTL activation converts LFA-1 from a low-avidity state to a high-avidity state 15 Formation of a conjugate between a CTL and target cell and reorientation of CTL cytoplasmic granules 2 min 16 10 min CTL-mediated pore formation in target-cell membrane 17 18 Experimental demonstration that CTLs use Fas and perforin pathways 19 All of the CTL-mediated killing they observed could be traced to the action of perforin-dependent killing, Fas-mediated killing, or a combination of the two. No other mechanism was detected. 20 p.358, right column Two pathways of target-cell apoptosis stimulated by CTLs mannose 6-phosphate receptors 21 Outline 22 Effector Responses General Properties of Effector T Cells Cytotoxic T Cells Natural Killer Cells NKT cells Antibody-Dependent Cell-Mediated Cytotoxicity Experimental Assessment of Cell-Mediated Cytotoxicity 23 Family of RAG-1 KO mice These mice have no adaptive immunity because they lack T and B cells. 24 NK cells differ from CTLs in several significant ways 1. 2. 3. 25 NK cells do not express antigen specific T-cell receptors or CD3. Recognition of target cells by NK cells is not MHC restricted. NK-cell activity does not increase after a second injection with the same tumor cells. In other words, the NK-cell response generates no immunologic memory. p.362, left column Opposing-signals model of how cytotoxic activity of NK cells is restricted to altered self-cells. 26 MHC-KIR gene combinations influence health Human KIR A haplotype 27 28 Outline 29 Effector Responses General Properties of Effector T Cells Cytotoxic T Cells Natural Killer Cells NKT cells Antibody-Dependent Cell-Mediated Cytotoxicity Experimental Assessment of Cell-Mediated Cytotoxicity NKT cells NKT cells is considered part of the innate im mune system. The T-cell receptor on the human NKT cell is invariant. The TCR on NKT cells does not recognize MHC-bound peptides NKT cells do not form memory cells NKT cells do not express T-cell markers but do express NK-cell markers 30 p.364-365 Outline 31 Effector Responses General Properties of Effector T Cells Cytotoxic T Cells Natural Killer Cells NKT cells Antibody-Dependent Cell-Mediated Cytotoxicity Experimental Assessment of Cell-Mediated Cytotoxicity 32 Outline 33 Effector Responses General Properties of Effector T Cells Cytotoxic T Cells Natural Killer Cells NKT cells Antibody-Dependent Cell-Mediated Cytotoxicity Experimental Assessment of Cell-Mediated Cytotoxicity Experimental Assessment of CellMediated Cytotoxicity 1. 2. 3. 34 The mixed-lymphocyte reaction (MLR) is an in vitro system for assaying TH-cell proliferation in a cell mediated response Cell-mediated lympholysis (CML) is an in vitro assay of effector cytotoxic function The graft-versus host reaction (GVH) in experimental animals provides an in vivo system for studying cell-mediated cytotoxicity. 35 Curve 0 = no class II MHC differences Curve 1 = one class II MHC difference Curve 2 = two class II MHC differences 36 37 CTL or NK cells activity assay 1.Cr-51 release assay (sample cpm ─ spontaneous cpm) (maximal cpm ─ spontaneous cpm) 100% The GVH Reaction Is an Indication of Cell-Mediated Cytotoxicity The recipients, especially neonatal ones, often exhibit weight loss. The intensity of a GVH reaction can be assess ed by calculating the spleen index as follows: 39 p.368, left column Outline 40 Effector Responses General Properties of Effector T Cells Cytotoxic T Cells Natural Killer Cells NKT cells Antibody-Dependent Cell-Mediated Cytotoxicity Experimental Assessment of Cell-Mediated Cytotoxicity Study question You have a monoclonal antibody specific for LFA -1.You perform CML assays of a CTL clone, using target cells for which the clone is specific, in the presence and absence of this antibody. Predict the relative amounts of 51Cr released in the two assays. Explain your answer. 41 Study question 42 A mouse is infected with influenza virus. How could you assess whether the mouse has TH and TC cells specific for influenza? Explain why NK cells from a given host will kill many types of virus-infected cells but do not kill normal cells from that host. 43
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