Abstracts (complete list) - Wissenschaft Online

Nicole Warnecke, Burkhart Schraven, Luca Simeoni
Analysis of TCR-mediated MAPK activation in primary T cells.
The mitogen-activated protein kinase (MAPK) family includes three major wellcharacterized
groups of kinases: the extracellular signal-regulated protein kinases
(ERK), the p38 MAP kinases and the c-Jun NH2-terminal kinases (JNK). In immune
cells, MAPKs preside to the regulation of lymphocyte development as well as to both the
innate and the adaptive immune responses. T cells possess multiple possible ways to
activate MAPKs. Previous data had suggested that RasGRP is required for ERK activation
and positive selection while Grb2 regulates another branch of the TCR-mediated
signaling cascade leading to JNK and p38 activation and negative selection in the
thymus. To assess how MAPKs are activated in peripheral T lymphocytes, we performed
RNA interference by using short interfering RNA (siRNA). Efficient downregulation of
RasGRP1, but not of Grb2 or Sos1, resulted in a severe reduction of TCR-mediated Erk
phosphorylation in human primary T cells. Thus, similar to thymocytes, also peripheral T
cells activate ERK via a pathway involving RasGRP. Surprisingly, when we suppress
Grb2 or Sos1 expression we found that ERK phosphorylation was enhanced. Finally, we
demonstrated that Grb2 and Sos1 are dispensable during TCR-mediated JNK and p38
phosphorylation in primary human T cells, thus indicating that JNK and p38 activation
occurs through different mechanisms in mature in comparison to immature T cells. In
summary, our data suggest that in primary T lymphocytes Grb2/Sos1 are not positive
regulators of MAPK activation but rather appear to be component of a negative
regulatory complex required to inhibit T-cell activation.