Evidence for a p21(ras)/Raf-1/MEK-1/ERK-2-independent pathway in stimulation of IL-2 gene transcription in human primary T lymphocytes

T cell stimulation leads to triggering of signals transmitted from the cell membrane to the nucleus through TCR/CD3 proteins. Characterization of thes e signals largely results from the use of cell lines stimulated with anti-C DB monoclonal antibodies. These studies have established that activation ca used a rapid increase in the formation of GTP-bound has, which stimulates t he mitogen-activated protein kinase pathway involving the extracellular-reg ulated kinase-2 (ERK-2) and activates the nuclear factor of activated T cel ls (NF-AT) that regulates interleukin-2 (IL-2) gene transcription. In the p resent study, we used human primary T cells, and we investigated the intrac ellular signals triggered by two different anti-CD3 monoclonal antibodies ( UCHT1 and X-35), which both strongly induce cell proliferation. We found th at, in contrast to the commonly used UCHT1, X-35 activated IL-2 gene transc ription without stimulation of the Raf-1/mitogen-activated ERK kinase-1 (ME K-1)/ERK-2 phosphorylation cascade; we also showed that X-35 stimulation, w hich triggers an ERK-2-independent pathway, does not involve activation of p21(ras). In addition to demonstrating that activation of p21(ras) and of i ts Raf-1/MEK-1/ERK-2 effector pathway is not an event obligatorily triggere d upon TCR/CD3 ligation, these results provide the first evidence of the ex istence of a p21(ras)/ERK-2-independent pathway for IL-2 gene transcription in human primary T lymphocytes.