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

2. 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.

3. Tumor-Cell Destruction by a CTL

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.

11. Quantitation of CTL by MHC Tetramers

12. 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-

13. Time Course of Viral Infection

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 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 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

17. Ab-Dependent Cell-Mediated
Cytotoxicity (ADCC)