Distinct Effects of STAT5 Activation on CD4+ and CD8+ T Cell Homeostasis: Development of CD4+CD25+ Regulatory T Cells versus CD8+ Memory T Cells

Burchill, Matthew A.; Goetz, Christine; Prlic, Martin; O’Neil, Jennifer J.; Harmon, Ian R.; Bensinger, Steven J.; Turka, Laurence A.; Brennan, Todd; Jameson, Stephen C.; Farrar, Michael A.

doi:10.4049/jimmunol.171.11.5853

Cited by 193 publications

(218 citation statements)

References 71 publications

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“…Unlike CA-AKT, CA-STAT5 augmented the expression of CD27, IL-2/15Rβ chains, and BCL2. Thus, elevated STAT5 activity appears to greatly enhance the survival and homeostasis of all antigen-specific effector and memory CD8 T cells, which is consistent with the observation that mice made transgenic for STAT5 have significantly increased numbers of memory cells (40)(41)(42).…”

Section: Discussionsupporting

confidence: 71%

“…For secondary infection, C57BL/6 mice containing ∼2,500 P14 CD8 T cells were infected with 2 × 10 4 cfu recombinant Listeria monocytogenes i.v. that expresses the LCMV GP [33][34][35][36][37][38][39][40][41] epitope (strain XFL203, but referred to as Listeria-GP33) (3). All experiments were done with approved Institutional Animal Care and Use Committee protocols.…”

Section: Methodsmentioning

confidence: 99%

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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.

194

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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Section: Discussionsupporting

confidence: 71%

Section: Methodsmentioning

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.

194

191

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“…Paradoxically, strong T cell hyperproliferation and autoimmune diseases are observed in mice deficient for IL-2 or components of its receptor [20][21][22][23]. This unexpected pathology can be explained by a reduced number of Treg or their functional impairment [24][25][26][27][28][29], since transfer of wildtype Treg into neonatal IL-2R-deficient mice prevents disease development [24,26,28,30]. IL-2 mainly plays a role for the peripheral expansion and maintenance of Treg [1,18,31] rather than their thymic generation since Treg develop in IL-2-deficient mice [16,28].…”

Section: Il-2 Is Essential For Treg Homeostasismentioning

confidence: 99%

Regulation of CD4⁺CD25⁺ regulatory T cell activity: it takes (IL‐)two to tango

2005

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Although CD4 + CD25 + regulatory T cells (Treg) represent a well-characterized population of T cells with in vitro and in vivo suppressive capacity, the basic mechanisms of suppression are still not understood. The constitutive expression of the high-affinity receptor for IL-2 has raised the question about the role of IL-2 in Treg function. Here, we review recent data indicating that IL-2 is not only necessary for the homeostasis of Treg but is also critical for the activation of Treg function. Since Treg do not produce IL-2 by themselves, their capacity to utilize IL-2 secreted by other T cells appears to be an essential component of Treg biology. This indicates that Treg suppressive activity is controlled by interaction with activated target cells via the soluble mediator IL-2. In Treg, IL-2 has been identified as a potent inducer of the immunosuppressive cytokine IL-10, an important mediator of Treg suppression in vivo. The efficient capture of IL-2 by Treg may, under conditions of limited IL-2 supply, cause IL-2 deprivation of responder T cells. This competition can explain some of the currently discussed discrepancies between in vivo and in vitro activity of Treg.

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“…6D). To evaluate the functional role of STAT5, we transduced MPI cells with retroviruses expressing CD4 and a constitutively active form (caSTAT5) (22). The transduced cells expressed STAT5 in the nucleus and proliferated without GM-CSF at the same rate as cells transduced with a control CD4-expressing retrovirus in its presence ( Fig.…”

Section: Gm-csf-induced Stat5 Confers Self-renewing Capacity To Mpi Cmentioning

confidence: 99%

Nontransformed, GM-CSF–dependent macrophage lines are a unique model to study tissue macrophage functions

Fejér

Wegner

Győry

et al. 2013

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

131

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Significance Macrophages—cells crucially involved in defense against infections—exhibit, depending on their anatomical location, distinct biological properties. Studies of the underlying mechanisms are of scientific and clinical interest, but are hampered by the difficulty of obtaining primary tissue macrophages in sufficient numbers and purity. Here, we report the generation of nontransformed murine macrophages, which are similar to alveolar macrophages and can be grown continuously without change of phenotype and in unlimited amounts. Such macrophages helped us to recognize several innate immune properties of alveolar macrophages that are involved in the pathogenesis of infectious lung inflammation.

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Distinct Effects of STAT5 Activation on CD4+ and CD8+ T Cell Homeostasis: Development of CD4+CD25+ Regulatory T Cells versus CD8+ Memory T Cells

Cited by 193 publications

References 71 publications

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

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

Regulation of CD4⁺CD25⁺ regulatory T cell activity: it takes (IL‐)two to tango

Nontransformed, GM-CSF–dependent macrophage lines are a unique model to study tissue macrophage functions

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Distinct Effects of STAT5 Activation on CD4+ and CD8+ T Cell Homeostasis: Development of CD4+CD25+ Regulatory T Cells versus CD8+ Memory T Cells

Cited by 193 publications

References 71 publications

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

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

Regulation of CD4+CD25+ regulatory T cell activity: it takes (IL‐)two to tango

Nontransformed, GM-CSF–dependent macrophage lines are a unique model to study tissue macrophage functions

Contact Info

Product

Resources

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Regulation of CD4⁺CD25⁺ regulatory T cell activity: it takes (IL‐)two to tango