The Erk2 MAPK Regulates CD8 T Cell Proliferation and Survival

Abstract

The magnitude of T cell responses is determined by proliferation and survival decisions made by the responding cells. We now demonstrate that the Erk MAPK pathway plays a critical role in these cell fate decisions within CD8 T cells. While Erk1 is dispensable for all aspects of CD8 T cell activation, Erk2 is required for the proliferation of CD8 T cells activated in the absence of costimulation. Surprisingly, Erk2 is not required for proliferation following the addition of a costimulatory signal in vitro, or upon viral infection in vivo, but regulates the size of the responding population by enhancing cell survival. An important component of this Erk2-derived signal is the transcriptional regulation of Bcl-2 family members Bcl-xL and Bim, and impaired Erk2-deficient CD8 T cell survival can be rescued by genetic ablation of Bim. These studies ascribe multifaceted functions specific to Erk2 in CD8 T cell activation, proliferation, and survival.

Reduced Regulatory T Cell Diversity in NOD Mice Is Linked to Early Events in the Thymus

“…Considering the defective NOD nTreg TCR repertoire as an independent phenotype could be consistent with involvement of Lck. Indeed, Lck is a key component of TCR signal transduction in contrast with ERK, which is not required for T cell activation (42). However, because proliferation in CD3/CD28-stimulated NOD T cells is not decreased (7), we consider that alterations in this gene are unlikely to underlie any of the defects reported in the present study.…”

Activated T Cell Exosomes Promote Tumor Invasion via Fas Signaling Pathway

“…Although the Fas-mediated apoptosis after c-FLIP siRNA inhibition in B16 cells showed no difference compared with control siRNA, we cannot exclude that c-FLIP plays a role in the Fas resistance of B16 cells, because the effect of c-FLIP knock down is mild, and the expression of c-FLIP decreases only ∼50%. It was reported that activation of the ERK pathway and subsequent induction of antiapoptotic proteins, such as Bcl-2, play important roles in the survival of CD8 + T and NK cells (44,45) In B16 tumor cells stimulated by FasL + EXO, we found that Bcl-2 was upregulated after EXO stimulation, and specific inhibitors of ERK and NF-kB activation could decrease the expression of Bcl-2. But there was no increasing apoptosis in the B16 cells treated with Bcl-2 inhibitor compared with the group treated with DMSO or control, which suggests that Bcl-2 may not be involved in the Fas resistance of B16 tumor cells induced by FasL-expressed EXO (data not shown).…”

Erk1 and Erk2 are required for maintenance of hematopoietic stem cells and adult hematopoiesis

“…Although Erk2 is known to play a crucial role in T-cell development and activation, 9,11 the role of Erk1 in T-lineage cells remains controversial. 4,5,9,11 Importantly, the development and maintenance of Erk1-deficient T cells in an Erk1-sufficient background has never been examined. Our data suggest that both Erk1 and Erk2 are necessary for normal T-cell development/maintenance in vivo.…”

“…Genetic experiments argued that Erk1 is required for T-cell development, 4 although this observation is controversial. 5,9,11 T-cell-specific deletion of Erk2 also leads to defective T-lymphocyte maturation, suggesting that in some cellular contexts, ERK1 cannot compensate for ERK2. 9 By contrast, either Erk1 or Erk2 is sufficient for normal B-cell development, 12 although this process is markedly impaired in Erk1/2 doubly-deficient B cells.…”