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

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

Tumor-Cell Destruction by a CTL

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

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

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.

CTLs Use Fas and Perforin Pathways

What are the conclusions?

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.

Quantitation of CTL by MHC Tetramers

Natural Killer (NK) Cells 5 - 10% 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 IFNa, IFNb, and IL-12. normal in RAG-1, RAG-2, and SCID mice CD16+ (FcRIII), FasL+, TCR/CD3-

Time Course of Viral Infection

NK-Cell Receptors Activation Receptors: Inhibitory 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)

Opposing-signals Model of NK Cytotoxicity

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 TCRa & TCRb (Va24 -Ja18, Vb11) 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

Ab-Dependent Cell-Mediated Cytotoxicity (ADCC)