4 CTL-Mediated Killing of Target Cells perforin monomers&granzyme proteases
5 Cell-Mediated Pore Formation on Target Cells fuse with CTL memrelease of perforininsert into mem
6 Perforin Pore on a Red Blood Cell Perforin exhibits sequencehomology with C9, and thepores formed by perforin aresimilar to those observed incomplement-mediated lysis.The perforin pores facilitateentry of granzymes (serineproteases) into the cell.Granzymes activate an apop-totic pathway within thetarget cell.
9 CTLs could kill target cells in two ways: 1. Directional delivery of cytotoxic proteins(perforin & granzymes) that are releasedfrom CTLs and enter target cells.2. Interaction of the membrane-bound Fasligand on CTLs with the Fas receptor onthe surface of target cells.
12 Natural Killer (NK) Cells 5 - 10% of the recirculating lymphocyte populationno immunization is required, no memorya population of large granular lymphoid cellsproduce IFN, thus playing important roles in immuneregulation and influencing both innate and adaptive immunityconstitutively cytotoxic, always having large granulescytotoxicity depends on perforin and granzymesinvolved in the defense against viruses and tumorsactivity is stimulated by IFNa, IFNb, and IL-12.normal in RAG-1, RAG-2, and SCID miceCD16+ (FcRIII), FasL+, TCR/CD3-
14 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 thathave 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 polymorphicproducts of particular HLA loci)
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 TCRa & TCRb (Va24 -Ja18, Vb11)and NK cell markers- TCR does not recognize MHC-bound peptides, butrather a glycolipid presented by the nonpolymorphicCD1d molecule (also Chap. 8, p. 217)- No memory- Express few T cell markers, but NK cell markers