Biased activation of human T lymphocytes due to low extracellular pH is antagonized by B7/CD28 costimulation

Bosticardo, Marita; Ariotti, Silvia; Losana, Giuliana; Bernabei, Paola; Forni, Guido; Novelli, Francesco

doi:10.1002/1521-4141(200109)31:9<2829::aid-immu2829>3.0.co;2-u

Cited by 61 publications

(51 citation statements)

References 53 publications

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“…IL-2-stimulated lymphocyte motility was increased at pH 6.5 when compared to pH 7.1 [22]. T lymphocyte cell cycle entry in response to PHA stimulation was suppressed at low pH, but restored by CD28 co-stimulation [11]. Our present study demonstrated that intracellular signaling initiated by CD3 stimulation and ZAP-70 phosphorylation were enhanced at acidic pH, suggesting that a signal transduction system that results in ZAP-70 activation functions under acidic conditions.…”

Section: Discussionsupporting

confidence: 45%

“…These early events allow the increase of intracellular Ca 2+ , activation of MAPK or PKC, and result in IL-2 gene expression that induces functional differentiation or cell cycle entry [10]. It has been reported that cell cycle entry by PHA stimulation is attenuated by low extracellular pH [11], while other investigators have reported that acidosis suppresses T cell functions [2,12]. Thus, it is still unclear whether extracellular low pH impairs TCR signaling or not.…”

Section: Introductionmentioning

confidence: 99%

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Extracellular acidic environments induce phosphorylation of ZAP-70 in Jurkat T cells

Hirata¹,

Fukamachi²,

H³

et al. 2008

Immunology Letters

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Section: Discussionsupporting

confidence: 45%

Section: Introductionmentioning

confidence: 99%

Extracellular acidic environments induce phosphorylation of ZAP-70 in Jurkat T cells

Hirata¹,

Fukamachi²,

H³

et al. 2008

Immunology Letters

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“…Since human IFN-␥ is species specific, it seems likely that IFN-␥R2 surface expression on ST4 cells growing in vivo had increased. Indeed, we have shown that in an acidic pH, which is a typical feature of tumor growth in vivo, 51 IFN-␥R2 expression is up-regulated, 22 resulting in partial restoration of ST4 sensitivity to IFN-␥.…”

Section: Discussionmentioning

confidence: 95%

“…Besides T-cell receptor (TCR) engagement, 9,12 up-regulation of surface IFN-␥R2 in T cells may also be induced by serum deprivation, 5 exposure to nitric oxide (NO), 21 or low extracellular pH, 22 all of which increase expression of inducible nitric oxide synthase (iNOS) and NO production in macrophages. 23 This suggests that serum factors capable of blocking NO production play a critical role in maintaining low IFN-␥R2 expression in T lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

Iron regulates T-lymphocyte sensitivity to the IFN-γ/STAT1 signaling pathway in vitro and in vivo

Regis

Bosticardo

Conti

et al. 2005

Blood

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IntroductionInterferon-␥ (IFN-␥), produced by T and natural killer (NK) cells, is considered the principal effector cytokine of cell-mediated immunity and exerts its effects on target cells through a highaffinity receptor complex linked to a specific Janus kinase (Jak)/ signal transducer and activator of transcription (STAT) signaling cascade. 1,2 The IFN-␥ receptor (IFN-␥R) complex consists of 2 chains: an IFN-␥R1 binding chain and an IFN-␥R2 signaling chain. 1 The intracellular portions of the 2 chains provide the Jak1 and Jak2 docking sites. Upon phosphorylation, Jak1 and Jak2 activate STAT1: Following phosphorylation and dimerization, STAT1 is translocated into the nucleus where it activates transcription of numerous sets of IFN-␥-inducible genes. 2 The IFN-␥/STAT1 pathway plays an essential role in controlling the expansion of normal and neoplastic cell types of different origin. Activation of this pathway switches on many proapoptotic and antiproliferative genes such as interferon regulatory factor 1 (IRF1), p21 waf/cip , Fas and FasL, and activates caspases. [3][4][5][6][7][8][9][10] However, the signals transduced by IFN-␥ do not always induce apoptosis or block proliferation, and lymphoid cells become resistant to the antiproliferative effects of IFN-␥. Resting, malignant, or normal T cells that develop toward the T helper 1 (Th1) pathway become resistant to the antiproliferative effects of the IFN-␥/STAT1 pathway 9,11,12 or rather, IFN-␥ favors their proliferation and differentiation. [13][14][15] The refractoriness of T cells to the IFN-␥/STAT1 pathway has been attributed mainly to down-regulation of the IFN-␥R chains, especially IFN-␥R2, which protects these cells from the antiproliferative/proapoptotic effects of [16][17][18][19] Both IFN-␥-dependent and -independent mechanisms have been reported to downregulate IFN-␥R2 expression in T lymphocytes. During murine Th cell differentiation, IFN-␥ itself induces IFN-␥ resistance by down-regulating IFN-␥R2, 16 whereas in human T lymphocytes, IFN-␥R2 internalization occurs mostly in clathrin-coated pits independently from IFN-␥ 17 and is selectively induced by insulinlike growth factor 1 (IGF1). 20 Since the IFN-␥/STAT1 pathway is usually down-regulated in T lymphocytes, information on the mechanisms that maintain low IFN-␥R2 expression in these cells might prove useful for devising therapeutic approaches centered on selectively reinstating the IFN-␥/STAT1 apoptotic signaling pathway in autoreactive or neoplastic T cells.Besides T-cell receptor (TCR) engagement, 9,12 up-regulation of surface IFN-␥R2 in T cells may also be induced by serum deprivation, 5 exposure to nitric oxide (NO), 21 Among the plethora of factors present in serum, iron has profound effects on numerous critical cell functions, such as electron and oxygen transport, mitochondrial energy metabolism, and detoxification, thus requiring tight homeostatic regulation. 24 Iron binds to cytoplasmic iron regulatory protein 1 (IRP1) and IRP2 which in turn regulate expression of proteins such as fe...

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“…IFN-␥R2 is engulfed by the plasma membrane of T cells which respond very poorly to IFN-␥ [15,17,18]. TCR stimulation, serum deprivation, exposure to nitric oxide (NO), ␤-galactoside binding protein (␤-GBP) and low extracellular pH (pHe) induce cell surface accumulation of IFN-␥R2 and restore IFN-␥/STAT1-dependent apoptosis [15][16][17][18][19][20][21]. The demonstration of a T cell specific IFN-␥ independent internalization of IFN-␥R2, involving clathrincoated pit-mediated endocytosis [18], and the identification of insulin-like-growth factor-1 (IGF-1) and iron as major players in IFN-␥R2 internalization [22][23][24], have shed new light on the fine tuning of the IFN-␥/STAT1 pathway in T cells.…”

Section: Introductionmentioning

confidence: 99%

Expression of IFNγR2 mutated in a dileucine internalization motif reinstates IFNγ signaling and apoptosis in human T lymphocytes

et al. 2010

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Biased activation of human T lymphocytes due to low extracellular pH is antagonized by B7/CD28 costimulation

Cited by 61 publications

References 53 publications

Extracellular acidic environments induce phosphorylation of ZAP-70 in Jurkat T cells

Extracellular acidic environments induce phosphorylation of ZAP-70 in Jurkat T cells

Iron regulates T-lymphocyte sensitivity to the IFN-γ/STAT1 signaling pathway in vitro and in vivo

Expression of IFNγR2 mutated in a dileucine internalization motif reinstates IFNγ signaling and apoptosis in human T lymphocytes

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