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

Abstract

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.