Impaired CD8 T cell memory and CD4 T cell primary responses in IL-7Rα mutant mice

Osborne, Lisa C.; Dhanji, Salim; Snow, Jonathan W.; Priatel, John J.; Melissa, C.; Miners, M. Jill; Teh, Hung‐Sia; Goldsmith, Mark A.; Abraham, Ninan

doi:10.1084/jem.20061871

Cited by 96 publications

(140 citation statements)

References 53 publications

(93 reference statements)

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“…In all cases of single γ c cytokine deficiency, memory CD8 + T cells were detected, albeit at reduced levels (7,13,16,17,(36)(37)(38)(39). This reduced memory formation, however, might have been secondary to reduced T cell survival, as γ c cytokines promote homeostasis through enhanced expression of antiapoptotic Bcl2 family members (40).…”

Section: Discussionmentioning

confidence: 94%

“…Antigen-specific memory CD8 + T cells are detected in the absence of IL-2, IL-7, IL-5, or IL-21 (16,17,(36)(37)(38)(39). Moreover, adoptive transfer of P14 CD122 −/− cells (lacking IL-2Rβ) generates a pool of memory CD8 + T cells indicating that a combination of γ c cytokines are involved.…”

Section: Discussionmentioning

confidence: 95%

“…In contrast, γ c −/− TCR transgenic (Tg) mice on the Rag2 deficient background harbor monoclonal populations of naive T cells, thus providing an approach to study the role of γ c cytokines during immune responses (18,21). P14 TCR Tg mice that develop CD8 + αβ T cells specific for the envelope glycoprotein 33-41 (GP [33][34][35][36][37][38][39][40][41] ) of the lymphocytic choriomeningitis virus (LCMV) were crossed onto the Rag2 −/− γ c +/+ or Rag2 −/− γ c −/− background. In the absence of γ c , intrathymic development of P14 CD8 + SP T cells was strongly reduced and cells failed to accumulate in peripheral lymphoid organs ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…CFSE labeling was done by incubating cells for 10 min at 37°C with 5 μM CFSE in PBS 2% FCS. For the in vivo cytotoxicity assay, the fate of GP [33][34][35][36][37][38][39][40][41] peptide pulsed CFSE high -labeled (1 μM) and nonpulsed CFSE low -labeled (0.1 μM) splenocytes in Pfp −/− chimeric mice was analyzed (50).…”

Section: Methodsmentioning

confidence: 99%

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γ _c deficiency precludes CD8 ⁺ T cell memory despite formation of potent T cell effectors

Decaluwe

Taillardet

Corcuff

et al. 2010

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

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Several cytokines (including IL-2, IL-7, IL-15, and IL-21) that signal through receptors sharing the common γ chain (γ c ) are critical for the generation and peripheral homeostasis of naive and memory T cells. Recently, we demonstrated that effector functions fail to develop in CD4 + T cells that differentiate in the absence of γ c . To assess the role of γ c cytokines in cell-fate decisions that condition effector versus memory CD8 + T cell generation, we compared the response of CD8 + T cells from γ c + or γ c − P14 TCR transgenic mice after challenge with lymphocytic choriomeningitis virus. The intrinsic IL-7-dependent survival defect of γ c − naive CD8 + T cells was corrected by transgenic expression of human Bcl-2. We demonstrated that although γ c -dependent signals are dispensable for the initial expansion and the acquisition of cytotoxic functions following antigenic stimulation, they condition the terminal proliferation and differentiation of CD8 + effector T cells (i.e., KLRG1 high CD127 low short-lived effector T cells) via the transcription factor, Tbet. Moreover, the γ c -dependent signals that are critical for memory T cell formation are not rescued by Bcl2 overexpression. Together, these data reveal an unexpected divergence in the requirement for γ c cytokines in the differentiation of CD4 + versus CD8 + cytotoxic T lymphocytes.cytotoxic T lymphocyte | homeostasis | cytokine

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

γ _c deficiency precludes CD8 ⁺ T cell memory despite formation of potent T cell effectors

Decaluwe

Taillardet

Corcuff

et al. 2010

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

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“…These findings indicate that the process of contraction is not stochastic and that effector CD8 T cells have acquired distinct cell fates; however, it does not discard the possible role of cytokine withdrawal in the contraction of effector cells. IL-7Rα is functionally required for memory precursor survival and optimal memory CD8 T cell generation (3,4,16). However, forced IL-7Rα expression does not enhance memory CD8 T cell formation (17-19).…”

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.

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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Immunologic Memory: T Cells in Humans

2012

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Impaired CD8 T cell memory and CD4 T cell primary responses in IL-7Rα mutant mice

Cited by 96 publications

References 53 publications

γ _c deficiency precludes CD8 ⁺ T cell memory despite formation of potent T cell effectors

γ _c deficiency precludes CD8 ⁺ T cell memory despite formation of potent T cell effectors

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

Immunologic Memory: T Cells in Humans

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Impaired CD8 T cell memory and CD4 T cell primary responses in IL-7Rα mutant mice

Cited by 96 publications

References 53 publications

γ c deficiency precludes CD8 + T cell memory despite formation of potent T cell effectors

γ c deficiency precludes CD8 + T cell memory despite formation of potent T cell effectors

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

Immunologic Memory: T Cells in Humans

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γ _c deficiency precludes CD8 ⁺ T cell memory despite formation of potent T cell effectors

γ _c deficiency precludes CD8 ⁺ T cell memory despite formation of potent T cell effectors