Cell Cycle Progression following Naive T Cell Activation Is Independent of Jak3/Common γ-Chain Cytokine Signals

Shi, Min; Lin, Tsung H.; Appell, Kenneth C.; Berg, Leslie J.

doi:10.4049/jimmunol.0804339

Cited by 22 publications

(23 citation statements)

References 71 publications

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“…Additionally, genes up-regulated in the periphery were associated with TCR signaling and CD28 co-stimulation (Cluster 1, p=3.16×10 −7 and 1.37×10 −7 , respectively), while genes induced in TASPR TIL included inhibitory receptors, such as PD-1 (PDCD1, Cluster 12, Supplemental Table 3), and reflected an environment of strong TGF-β signaling (Cluster 2, p=4.9×10 −36 ). Suboptimal TCR and co-stimulation, PD-1, and TGF-β, are all known to restrict TIL function and to inhibit cell cycle progression (5, 52-54). …”

Section: Resultsmentioning

confidence: 99%

Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model

Waugh

Leach

Moore

et al. 2016

The Journal of Immunology

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Mechanisms of self-tolerance often result in CD8+ tumor-infiltrating lymphocytes (TIL) with a hypofunctional phenotype incapable of tumor clearance. Using a transplantable colon carcinoma model, we found that CD8+ T cells became tolerized in less than 24 hours in an established tumor environment. To define the collective impact of pathways suppressing TIL function, we compared genome-wide mRNA expression of tumor-specific CD8+ T cells from the tumor and periphery. Notably, gene expression induced during TIL hypofunction more closely resembled self-tolerance than viral-exhaustion. Differential gene expression was refined to identify a core set of genes that defined hypofunctional TIL; these data comprise the first “molecular profile” of tumor-specific TIL that are naturally responding and represent a polyclonal repertoire. The molecular profile of TIL was further dissected to determine the extent of overlap and distinction between pathways that collectively restrict T cell functions. As suggested by the molecular profile of TIL, protein expression of inhibitory receptor LAG-3 was differentially regulated throughout prolonged late-G1/early-S phase of the cell cycle. Our data may accelerate efficient identification of combination therapies to boost anti-tumor function of TIL specifically against tumor cells.

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Section: Resultsmentioning

confidence: 99%

Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model

Waugh

Leach

Moore

et al. 2016

The Journal of Immunology

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“…To test cooperation between TCR and IL-2R downstream signaling the transgenic mouse models and IL-2R-deficient T cells have been widely used with the assumption that intracellular signaling in these cells would be identical to that in normal T cells. Nevertheless, there is evidence that in knockout models other signaling may be engaged in cell activation that compensates the signaling switch off in cells in vivo [16, 17]. Little studies are available on intact primary T cells, and how antigen- and cytokine-evoked signals are timely coordinated under physiological conditions to induce the IL-2Rα expression is poorly investigated.…”

Section: Introductionmentioning

confidence: 99%

Time-Dependent Regulation of IL-2R α-Chain (CD25) Expression by TCR Signal Strength and IL-2-Induced STAT5 Signaling in Activated Human Blood T Lymphocytes

et al. 2016

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The expression of the IL-2R α-chain (IL-2Rα) is regulated at the transcriptional level via TCR- and IL-2R-signaling. The question is how to precede in time the activation signals to induce the IL-2Rα expression in native primary T cells. By comparing the effects of selective drugs on the dynamics of CD25 expression during the mitogen stimulation of human peripheral blood lymphocytes, we identified distinct Src- and JAK-dependent stages of IL-2Rα upregulation. PP2, a selective inhibitor of TCR-associated Src kinase, prevents CD25 expression at initial stages of T cell activation, prior to the cell growth. This early IL-2Rα upregulation underlies the T cell competence and the IL-2 responsiveness. We found that the activated with “weak” mitogen, the population of blood lymphocytes has some pool of competent CD25+ cells bearing a high affinity IL-2R. A distinct pattern of IL-2R signaling in resting and competent T lymphocytes has been shown. Based on the inhibitory effect of WHI-P131, a selective drug of JAK3 kinase activity, we concluded that in quiescent primary T lymphocytes, the constitutive STAT3 and the IL-2-induced prolonged STAT5 activity (assayed by tyrosine phosphorylation) is mostly JAK3-independent. In competent T cells, in the presence of IL-2 JAK3/STAT5 pathway is switched to maintain the higher and sustained IL-2Rα expression as well as cell growth and proliferation. We believe that understanding the temporal coordination of antigen- and cytokine-evoked signals in primary T cells may be useful for improving immunotherapeutic strategies.

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“…The T cell proliferative capacity and effector function in response to paraformaldehyde (PFA)-fixed CF5-and M68-stimulated BMDCs were studied. Infected BMDCs were cocultured with CFSE-labeled splenocytes in the presence of anti-CD3/ CD28 (31). At 96 h after coculture, CF5-and M68-mediated T cell proliferation was quantified, and similar increases between the two were recorded (Fig.…”

Section: Resultsmentioning

confidence: 99%

Host Immunity to Clostridium difficile PCR Ribotype 017 Strains

et al. 2014

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dClostridium difficile is an important nosocomial pathogen and the leading cause of antibiotic-associated diarrhea. Multilocus sequence typing indicates that C. difficile strains belong to five distinct genetic clades encompassing several PCR ribotypes (RT). Since their emergence in 2003, hypervirulent RT027 strains have been a major focus of research; in contrast, our current understanding of RT017-mediated disease pathogenesis lags far behind. In this study, we aimed to characterize host immunity to CF5 and M68, two genetically well-defined RT017 strains. Both strains engaged with host Toll-like receptor 2/6 (TLR2/6), TLR2-CD14, and TLR5 to similar extents in a model cell line. Despite this, CF5 mediated significantly greater dendritic cell (DC) interleukin-12 (IL-12), IL-27, and IL-10 immunity than M68. Both strains elicited similar IL-1␤ mRNA levels, and yet only M68 caused a marked increase in secretory IL-1␤. A CF5 cocultured-DC cytokine milieu drove an equipotent Th1 and Th17 response, while M68 promoted greater Th17 immunity. Human gastrointestinal ex vivo cytokine responses to both strains were characterized. Taken together, our data suggest that C. difficile strains mediate overlapping and yet distinct mucosal and DC/T cell immunity. Finally, toxin-driven IL-1␤ release supports the hypothesis that this cytokine axis is a likely target for therapeutic intervention for C. difficile infection.

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Cell Cycle Progression following Naive T Cell Activation Is Independent of Jak3/Common γ-Chain Cytokine Signals

Cited by 22 publications

References 71 publications

Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model

Molecular Profile of Tumor-Specific CD8+ T Cell Hypofunction in a Transplantable Murine Cancer Model

Time-Dependent Regulation of IL-2R α-Chain (CD25) Expression by TCR Signal Strength and IL-2-Induced STAT5 Signaling in Activated Human Blood T Lymphocytes

Host Immunity to Clostridium difficile PCR Ribotype 017 Strains

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