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Chapter 14 Cell-Mediated Cytotoxic Responses Jan 2, 2007.

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Presentation on theme: "Chapter 14 Cell-Mediated Cytotoxic Responses Jan 2, 2007."— Presentation transcript:

1 Chapter 14 Cell-Mediated Cytotoxic Responses Jan 2, 2007

2 Cytotoxic Cells Cytotoxic T Lymphocyte (CTL, T C ) Natural Killer Cell (NK cell) Natural Killer T Cell (NKT cell) Ab-dependent Cell-mediated Cytotoxicity (ADCC): Macrophage, Neutrophil, eosinophil, etc.

3 Tumor-Cell Destruction by a CTL CTL tumor cell

4 CTL-Mediated Killing of Target Cells perforin monomers & granzyme proteases

5 Cell-Mediated Pore Formation on Target Cells fuse with CTL mem release of perforin insert into mem

6 Perforin Pore on a Red Blood Cell - Perforin exhibits sequence homology with C9, and the pores formed by perforin are similar to those observed in complement-mediated lysis. - The perforin pores facilitate entry of granzymes (serine proteases) into the cell. - Granzymes activate an apop- totic pathway within the target cell.

7 CTLs Use Fas and Perforin Pathways

8 What are the conclusions?

9 CTLs could kill target cells in two ways: 1. Directional delivery of cytotoxic proteins (perforin & granzymes) that are released from CTLs and enter target cells. 2. Interaction of the membrane-bound Fas ligand on CTLs with the Fas receptor on the surface of target cells.

10

11 Quantitation of CTL by MHC Tetramers

12 Natural Killer (NK) Cells % of the recirculating lymphocyte population - no immunization is required, no memory - a population of large granular lymphoid cells - produce IFN , thus playing important roles in immune regulation and influencing both innate and adaptive immunity - constitutively cytotoxic, always having large granules - cytotoxicity depends on perforin and granzymes - involved in the defense against viruses and tumors - activity is stimulated by IFN , IFN , and IL normal in RAG-1, RAG-2, and SCID mice - CD16 + (Fc  RIII), FasL +, TCR/CD3 -

13 Time Course of Viral Infection

14 NK-Cell Receptors Activation Receptors: - e.g., NKG2D, CD94/NKG2C (C-type lectins) others are CD2, CD16, CD244, NKp30, NKp44, NKp46 - recognizing MIC-A & MIC-B proteins induced on cells that have been stressed by infection, heat or trauma. Inhibitory Receptors: - C-type-lectin-inhibitory receptors (CLIR) e.g., CD94/NKG2A in humans (recognizing HLA-E with HLA peptides) - Killer-cell Ig-like receptors (KIR) (> 50 members; specific for one or a limited number of polymorphic products of particular HLA loci)

15 Opposing-signals Model of NK Cytotoxicity

16 NKT Cells CTL: adaptive immunity component (using TCR for Ag recognition) NK cell: innate immunity component (using KIR & lectin-like receptor for Ag recognition) NKT cell: expressing invariant TCR  & TCR   V   J   V    and NK cell markers - TCR does not recognize MHC-bound peptides, but rather a glycolipid presented by the nonpolymorphic CD1d molecule (also Chap. 8, p. 217) - No memory - Express few T cell markers, but NK cell markers

17 Ab-Dependent Cell-Mediated Cytotoxicity (ADCC)


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