Transcriptional Mechanisms Underlying Lymphocyte Tolerance

Macián, Fernando; García-Cózar, Francisco; Im, Sin Hyeog; Horton, Heidi F.; Byrne, Michael C.; Rao, Anjana

doi:10.1016/s0092-8674(02)00767-5

Cited by 625 publications

(739 citation statements)

References 61 publications

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“…One could speculate that such a suboptimal stimulation somehow leads to a reduction of Ca 2+ influx through CRAC channels, thereby inducing tolerance, which in turn would suppress activation and proliferation of the cells after optimal TCR stimulation. In support of this hypothesis, changes in [Ca 2+ ] i signaling have been shown to be important for the induction of tolerance in T cells [22,23].…”

Section: Analysis Of Calcium Signals In T Lymphocytes Of Inflamed Andmentioning

confidence: 84%

Two‐photon analysis of calcium signals in T lymphocytes of intact lamina propria from human intestine

et al. 2004

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Lamina propria (LP) T cells of the human intestinal mucosa usually do not develop systemic immune responses despite permanent exposure to foreign antigens. The mechanisms maintaining this hyporeactivity in the normal gut are poorly understood. It is, at present, not clear what role the microenvironment of the mucosa plays for low T cell reactivity and in the pathogenesis of mucosal inflammation. Despite the importance of cytosolic Ca 2+ signals for T lymphocyte activation, intracellular Ca 2+ concentration measurements have so far only been performed in dissociated T cells, following disruption of the microenvironment. We used two-photon technology to measure Ca 2+ signals in identified T lymphocytes within the intact mucosa to minimize impact on tissue integrity while preserving the cellular microenvironment. We show that Ca 2+ signals in LP T cells correlate with the hyporeactivity of T cells in the intestinal immune system and furthermore link Ca 2+ signals with inflammatory bowel disease. Our data implicate that Ca 2+ signals in LP T cells do not depend on the microenvironment of the intact mucosa, since they are very similar to Ca 2+ signals in dissociated LP T cells.

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Section: Analysis Of Calcium Signals In T Lymphocytes Of Inflamed Andmentioning

confidence: 84%

Two‐photon analysis of calcium signals in T lymphocytes of intact lamina propria from human intestine

et al. 2004

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“…The Rao group [23] has proposed that sustained Ca 2+ signaling in isolation leads to the preferential induction of an inhibitory genetic program while T cell activation with costimulation leads to maximal AP-1 activation and the subsequent induction of activators of T cell function. Thus, we wanted to determine how inhibitors of T cell function (Egr-2 and Egr-3) and activators of T cell function (Egr-1 and NAB2) fit this paradigm.…”

Section: Resultsmentioning

confidence: 99%

“…Stimulating T cells with ionomycin leads to the Ca 2+ -induced activation of NF-AT and the preferential upregulation of a TCR-induced negative regulatory gene expression profile (T cell anergy) [23]. Thus, we stimulated purified naive CD4 + TCR-transgenic T cells from 5CC7 mice on a Rag -/-background with either ionomycin alone to activate NF-AT or with PMA to activate the Ras-MAP-kinase pathway.…”

Section: Resultsmentioning

confidence: 99%

Opposing regulation of T cell function by Egr‐1/NAB2 and Egr‐2/Egr‐3

et al. 2008

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TCR-induced NF-AT activation leads to the up-regulation of multiple genes involved in T cell anergy. Since NF-AT is also involved in T cell activation, we have endeavored to dissect TCR-induced activating and inhibitory genetic programs. This approach revealed roles for the early growth response (Egr) family of transcription factors and the Egr coactivator/corepressor NGFI-A-binding protein (NAB)2 in regulating T cell function. TCR-induced Egr-1 and NAB2 enhance T cell function, while Egr-2 and Egr-3 inhibit T cell function. In this report, we demonstrate that Egr-2 and Egr-3 are induced by NF-AT in the absence of AP-1, while Egr-1 and NAB2 both require AP-1-mediated transcription. Our data suggest that Egr-3 is upstream of Egr-2, and that mechanistically Egr-2 and Egr-3 suppress Egr-1 and NAB2 expression. Functionally, T cells from Egr-2 and Egr-3 null mice are hyperresponsive while T cells from Egr-3 transgenic, overexpressing mice are hyporesponsive. Furthermore, an in vivo model of autoimmune pneumonitis reveals that T cells from Egr-3 null mice hasten death while Egr-3-overexpressing T cells cause less disease. Overall, our data suggest that just as the Egr/NAB network of genes control cell fate in other systems, TCR-induced Egr-1, 2, 3 and NAB2 control the fate of antigen recognition in T cells.

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“…InsP 3 releases Ca 2+ from internal Ca 2+ stores and the Ca 2+ store depletion activates store-operated Ca 2+ channels called Ca 2+ release-activated Ca 2+ (CRAC)/ORAI channels in T cells [7,8]. There is no doubt that Ca 2+ signaling is required for clonal expansion (proliferation) of T cells as well as for the generation and activation of effector cells [9][10][11]. There is also clear evidence that CRAC channels provide the only pathway for Ca 2+ entry in T cells [12,13].…”

Section: Introductionmentioning

confidence: 99%

“…While the importance of Ca 2+ entry via STIM/ORAI/ CRAC for T cell proliferation, activation and even tolerance is undisputed [10,[13][14][15]23], very little is known about the correlation between T cell activation following formation of the IS and the amplitude and kinetics of the intracellular Ca 2+ concentration. This is surprising given the potential to control the adaptive immune response through changes in free intracellular calcium concentration ([Ca 2+ ] i ) during T cell activation.…”

Section: Introductionmentioning

confidence: 99%

Calcium dependence of T cell proliferation following focal stimulation

et al. 2007

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Clonal T cell expansion through proliferation is a central process of the adaptive immune response. Apoptosis of activated T cells is required to avoid chronic inflammation. T cell proliferation and apoptosis are often analyzed with stimuli that do not induce formation of a functional immunological synapse. Here we analyze the Ca 2+ dependence of proliferation and apoptosis in primary human CD4 + T cells following stimulation with anti-CD3/anti-CD28-coated beads, which induce a tight interaction similar to the immunological synapse. We found this focal stimulation to be much more efficient for stimulating IL-2 production and proliferation than non-focal TCR stimuli. Surprising little Ca 2+ entry through Ca 2+ channels was required for T cell proliferation. Transient free intracellular calcium concentration ([Ca 2+ ] i ) elevations of up to 220 nM from a baseline level of around 40 nM were sufficient for maximal proliferation in primary human CD4 + T cells. We also show that proliferation was very Ca 2+ sensitive in the range 90-120 nM, whereas apoptosis was basically constant for [Ca 2+ ] i levels of 90-120 nM. We conclude that very small changes in [Ca 2+ ] i can dramatically change the ratio between proliferation and apoptosis, thus keeping the balance between overshooting and inefficient immune responses.

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Transcriptional Mechanisms Underlying Lymphocyte Tolerance

Cited by 625 publications

References 61 publications

Two‐photon analysis of calcium signals in T lymphocytes of intact lamina propria from human intestine

Two‐photon analysis of calcium signals in T lymphocytes of intact lamina propria from human intestine

Opposing regulation of T cell function by Egr‐1/NAB2 and Egr‐2/Egr‐3

Calcium dependence of T cell proliferation following focal stimulation

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