How are Cytotoxic T lymphocytes activated?
Most Cytotoxic T lymphocytes (CTLs) are CD8+ T cells. A naïve CD8+ CTL first develops into a memory CD8+ CTL after engagement with an APC, usually a DC, which has been stimulated by an activated CD4+ helper T cell in lymphoid tissues. The CD4-activated DC presents intracellular antigen (e.g., viruses) on its surface in association with MHC-encoded HLA class I molecules. These engage with the CTL TCR (signal 1) as well as costimulatory molecules (signal 2), resulting in an activated CTL. On activation, CTLs divide and circulate to find infected/abnormal cells to kill. The CTL (CD8+) TCR specific for the antigen binds the HLA class I molecule containing the foreign peptide. Several other adhesion molecules also contribute to this interaction (e.g., CD2 [LFA-2]-CD58 [LFA-3]). Cytotoxicity occurs by:
• Granule exocytosis: granules containing granzymes from the CTL enter the target cell through pores in its membrane created by perforin. These proteases can cause apoptosis of the target cells.
• Fas ligand (FasL)-induced apoptosis: FasL on the CTL binds to Fas (CD95) on the target cell causing apoptosis.
CTLs can secrete cytokines (IFN-γ) and recruit macrophages into the area to augment the immune response. One CTL can lyse multiple cells.
