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 % 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 -
Time Course of Viral Infection
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)
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 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