The Anti-Apoptotic Bcl-2 Family Member Mcl-1 Promotes T Lymphocyte Survival at Multiple Stages

Abstract

T lymphocyte development and function are tightly regulated by the intrinsic death pathway through members of the Bcl-2 family. Genetic studies have demonstrated that the Bcl-2 family member Mcl-1 is an important anti-apoptotic protein in the development of multiple cell types including T lymphocytes. However, the expression pattern and anti-apoptotic roles of Mcl-1 in T lymphocytes at different developmental stages remain to be fully determined. In this study, we examined the expression pattern of Mcl-1 in different populations of T cells at the single-cell level and found that Mcl-1 protein is constitutively expressed in all T cell populations and up-regulated upon TCR stimulation. We then investigated the role of Mcl-1 in the survival of these different populations by conditionally deleting Mcl-1 at various T cell stages. Our results show that Mcl-1 is required for the survival of double-negative and single-positive thymocytes as well as naive and activated T cells. Furthermore, we demonstrate that Mcl-1 functions together with Bcl-xL to promote double-positive thymocyte survival. Thus, Mcl-1 is a critical anti-apoptotic factor for the survival of T cells at multiple stages in vivo.

TAK1–JNK Axis Mediates Survival Signal through Mcl1 Stabilization in Activated T Cells

“…2C). This finding is consistent with the reports demonstrating the redundant role of Mcl1 and Bclx L in antiapoptotic function (30,38).…”

“…2D and data not shown). Instead, we found that JNK activity correlates well with phosphorylation status and stability of Mcl1, an antiapoptotic protein expressed in activated T cells (29)(30)(31)(32). We concluded that the IL-2R-mediated TAK1-JNK axis regulates the survival of activated T cells through stabilization of Mcl1, although its molecular mechanism remains elusive.…”

“…Given the pivotal role of Mcl1 in protecting activated T cells from apoptosis (29)(30)(31)(32) and that MAPK is able to phosphorylate and stabilize Mcl1 (33, 34), we reasoned that treatment with LL-Z1640-2 result in the impaired expression of Mcl1 via inactivation of TAK1-JNK axis. To examine this hypothesis, we evaluated the expression levels of antiapoptotic molecules in the presence of LL-Z1640-2 and found that Mcl1 expression was substantially reduced by the blockade of the TAK1 pathway (Fig.…”

Elevated Mcl-1 inhibits thymocyte apoptosis and alters thymic selection

“…Mcl-1 is expressed at comparable levels in all of these cell subsets. 11 Bim is the BH3-only protein most critical for thymocyte deletion: thymocytes lacking Bim were refractory to apoptosis induced by stimulation with CD3 antibodies and Bim deficiency in transgenic (tg) mice expressing autoreactive TCRs severely impaired thymocyte apoptosis. 12,13 Studies using tg mice showed that overexpression of Bcl-2 [13][14][15][16] or Bcl-x L 8 enhanced the survival of thymocytes (and mature T cells) exposed to diverse cellular stresses.…”

MYB IS Required for B-Selection During Thymopoises

“…However, little is actually understood about mechanisms that suppress or enforce cell death downstream of the pre-TCR but the balance of pro-apoptotic and anti-apoptotic Bcl-2 family members appears to play a significant role during β-selection [86,95,103,104]. In particular, repression of Bid and Bim expression has recently been reported to be important for survival during β-selection [95] and Bcl2A1 expression is increased during β-selection [86].…”