Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis

Wojciechowski, Sara; Tripathi, Pulak; Bourdeau, Tristan; Acero, Luis; Grimes, H. Leighton; Katz, Jonathan D.; Finkelman, Fred D.; Hildeman, David A.

doi:10.1084/jem.20070618

Cited by 199 publications

(237 citation statements)

References 59 publications

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“…Bim-1 is a proapoptotic antagonist of Bcl-2 (49), and we noted a decrease, which is indicative of increased susceptibility to apoptosis, in the ratio of Bcl-2/Bim-1 expression levels in WT PbA-infected spleens (Fig. 6D) (49). Bcl-2 downregulation in the presence of PbMIF was confirmed further by immunoblotting of spleen lysates from WT PbA-and mifKO PbA-infected mice at day 5 post infection (Fig.…”

Section: Pmif Increases Inflammatory Cytokine Production and Cd4 T-cellmentioning

confidence: 60%

APlasmodium-encoded cytokine suppresses T-cell immunity during malaria

Sun¹,

Holowka²,

Song³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

116

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The inability to acquire protective immunity against Plasmodia is the chief obstacle to malaria control, and inadequate T-cell responses may facilitate persistent blood-stage infection. Malaria is characterized by a highly inflammatory cytokine milieu, and the lack of effective protection against infection suggests that memory T cells are not adequately formed or maintained. Using a genetically targeted strain of Plasmodium berghei, we observed that the Plasmodium ortholog of macrophage migration inhibitory factor enhanced inflammatory cytokine production and also induced antigen-experienced CD4 T cells to develop into short-lived effector cells rather than memory precursor cells. The short-lived effector CD4 T cells were more susceptible to Bcl-2–associated apoptosis, resulting in decreased CD4 T-cell recall responses against challenge infections. These findings indicate that Plasmodia actively interfere with the development of immunological memory and may account for the evolutionary conservation of parasite macrophage migration inhibitory factor orthologs.

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Section: Pmif Increases Inflammatory Cytokine Production and Cd4 T-cellmentioning

confidence: 60%

APlasmodium-encoded cytokine suppresses T-cell immunity during malaria

Sun¹,

Holowka²,

Song³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

116

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“…Together, these findings suggest that defective AKT signaling alone is not the primary cause of terminal effector cell apoptosis following infection, because constitutive AKT activation did not hinder cell death. Instead, it induced a negative feedback loop that repressed the expression of IL-7 and IL-15 cytokine receptors and impaired STAT5 signaling and BCL2 expression (6). These results do not necessarily rule out that the basal levels of AKT activity are important for memory T-cell survival but rather underscore that the proper balance of AKT signaling is critical for optimal memory CD8 T-cell formation and function.…”

Section: Impairment Of Memory Cd8 T-cell Survival and Function By Conmentioning

confidence: 63%

“…Activation of these two pathways results in decreased levels of proapoptotic proteins, increased expression of antiapoptotic genes such as BCL2, and activation of cellular growth and proliferation pathways regulated by mTOR and cyclins (5). The balance between these pro-and antiapoptotic factors controls the survival of CD8 T cells after immunization (6).…”

mentioning

confidence: 99%

Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival

Hand

Cui²,

Jung³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

192

191

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During viral infection, effector CD8 T cells contract to form a population of protective memory cells that is maintained by IL-7 and IL-15. The mechanisms that control effector cell death during infection are poorly understood. We investigated how short-and long-lived antiviral CD8 T cells differentially used the survival and cell growth pathways PI3K/AKT and JAK/STAT5. In response to IL-15, long-lived memory precursor cells activated AKT significantly better than shortlived effector cells. However, constitutive AKT activation did not enhance memory CD8 T-cell survival but rather repressed IL-7 and IL-15 receptor expression, STAT5 phosphorylation, and BCL2 expression. Conversely, constitutive STAT5 activation profoundly enhanced effector and memory CD8 T-cell survival and augmented homeostatic proliferation, AKT activation, and BCL2 expression. Taken together, these data illustrate that effector and memory cell viability depends on properly balanced PI3K/AKT signaling and the maintenance of STAT5 signaling.apoptosis | cytokine signaling | interleukin 15 | interleukin 7 | lymphocytic choriomeningitis virus M emory CD8 T cells form from a much larger effector population and provide long-term immunity against subsequent infections via rapid reactivation. The exact biochemical mechanism governing the survival of memory cells and apoptosis of the majority of effector cells is not well understood (1). As naïve T cells differentiate into effector and memory T cells, cytokines play a key role in their differentiation and survival. IL-2, IL-7, and IL-15 promote the expansion and survival of activated T cells (2). As memory CD8 T cells form following acute viral infection, two of these cytokines, IL-15 and IL-7, direct memory T cell survival and homeostasis (3, 4). Downstream of their specific receptors, IL-7 and IL-15 activate two primary pathways: janus kinase/signal transducer and activator of transcription 5 (JAK/STAT5) and phosphoinositide 3-kinase (PI3K)/AK-transforming (AKT). Activation of these two pathways results in decreased levels of proapoptotic proteins, increased expression of antiapoptotic genes such as BCL2, and activation of cellular growth and proliferation pathways regulated by mTOR and cyclins (5). The balance between these pro-and antiapoptotic factors controls the survival of CD8 T cells after immunization (6).Early models predicted that effector CD8 T-cell contraction was a result of deprivation of T-cell growth factor cytokines that wane during the later stages of infection and that survival was determined via the stochastic interaction of effector T cells with these cytokines. However, effector CD8 T cells are a heterogeneous population composed of cells with varying intrinsic potential for survival and differentiation into memory cells (3,7,8). During several types of infections [such as lymphocytic choriomeningitis virus (LCMV), vesicular stomatitis virus (VSV), Listeria monocytogenes, and Toxoplasma gondii], most of the effector CD8 T cells terminally differentiate and become short-lived, but ...

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“…More precisely, the balance between the proapoptotic Bim and the antiapoptotic Bcl-2 and Bcl-XL controls Tm survival (10)(11)(12)(13), and a direct inhibition of Bcl-2 and Bcl-XL reduced the number of T cells with a memory phenotype in mice (14). Therefore, we hypothesized that a pharmacological modulation of the intrinsic apoptosis pathway using recently developed proapoptotic small molecule Bcl-2 inhibitors, such as ABT-737 and ABT-263 (navitoclax), might represent a promising opportunity to control Tm responses (15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Bcl-2 Inhibition to Overcome Memory Cell Barriers in Transplantation

Cippà

Gabriel

Kraus

et al. 2014

American Journal of Transplantation

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y Both authors contributed equally.Memory T cells (Tm) represent a major barrier for immunosuppression and tolerance induction after solid organ transplantation. Taking into consideration the critical role of the intrinsic apoptosis pathway in the generation and maintenance of Tm, we developed a new concept to deplete alloreactive Tm by targeting Bcl-2 proteins. The small-molecule Bcl-2/Bcl-XL inhibitor ABT-737 efficiently induced apoptosis in alloreactive Tm in vitro and in vivo and prolonged skin graft survival in sensitized recipients. A short course of ABT-737 induction therapy prevented Tm-mediated resistance in a donor-specific transfusion model and allowed mixed chimerism induction across Tm barriers. Since Bcl-2 inhibitors yielded encouraging safety results in cancer trials, this novel approach might represent a substantial advance to prevent allograft rejection and induce tolerance in sensitized recipients.

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Bim/Bcl-2 balance is critical for maintaining naive and memory T cell homeostasis

Cited by 199 publications

References 59 publications

APlasmodium-encoded cytokine suppresses T-cell immunity during malaria

APlasmodium-encoded cytokine suppresses T-cell immunity during malaria

Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival

Bcl-2 Inhibition to Overcome Memory Cell Barriers in Transplantation

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