CD8⁺ T cell cytolytic activity independent of mitogen-activated protein kinase/extracellular regulatory kinase signaling (MAP kinase/ERK)

Cytotoxicity is a major effector function of CD8⁺ T cells. Although mitogen-activated protein kinase (MAP kinase)/extracellular regulatory kinase (ERK) activity is indispensable for cytotoxic activity of most CD8⁺ T cells a portion of CD8 T cells appears resistant to MEK inhibition as cytotoxicity of bulk cultures was partially preserved in the presence of a MEK inhibitor. We have also identified a long-term CD8⁺ T cell line with unaltered cytolytic activity after prevention of ERK activation. Antigen-induced microtubule organizing center (MTOC) reorientation was not prevented in this CD8⁺ cell line by MEK inhibition, in sharp contrast to the MTOC reorientation prevention in a CD8⁺ T cell clone with MEK inhibition-sensitive cytolytic activity. These findings suggest that resistance of lysis to MEK inhibition may be due to a lack of ERK control over MTOC reorientation in some CD8⁺ T cells. Thus, there appears to be a heterogeneity of ERK-regulated cytolytic activity in CD8⁺ T cells, most likely resulting from a differential control of ERK over MTOC motility.