Regulation of T Cell Deletion by Heparan Sulfate-Bound Interleukin 2.

Wrenshall, Lucile E.; Miller, John O.; Ford, Harris; Wander, Nepheli; Tamura, Ryuichi; Platt, Jeffrey L.

doi:10.1097/00007890-200004271-01028

Cited by 39 publications

(62 citation statements)

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“…The reason for the individual variability in the degree of postculture CD28 modulation is not clear at this time. However, TNF␣ is known to interact with mannose diesters of glycan moieties from membrane proteins (40), a biochemical property of many cytokines that promotes the extension of cytokine biologic half-life (41,42). Hence, it is possible that the observed down-regulation, versus up-regulation, of CD28 on the T cells in some patients (even after overnight culture) ( Figure 3A) could be instances when TNF␣ became sequestered in the T cell membrane glycocalyx and remained biologically active for some period of time.…”

Section: Discussionmentioning

confidence: 99%

Modulation of CD28 expression with anti–tumor necrosis factor α therapy in rheumatoid arthritis

Bryl¹,

Vallejo²,

Matteson³

et al. 2005

Arthritis & Rheumatism

125

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Objective. The immune system of patients with rheumatoid arthritis (RA) is characterized by the accumulation of CD4؉ T cells deficient in CD28 expression and the up-regulation of tumor necrosis factor ␣ (TNF␣). Previous in vitro studies have shown that TNF␣ induces transcriptional silencing of the CD28 gene. Because reduced expression of CD28 in T cells compromises immunocompetence, we examined whether CD28 expression is reduced in patients with RA in vivo and whether the reduction is related to TNF␣.Methods. Patients with RA and age-matched individuals were recruited. Peripheral blood mononuclear cells were stained for CD3, CD4, CD8, CD28, TNF receptor I (TNFRI), and TNFRII, and analyzed by quantitative flow cytometry. The number of CD28 and TNFR molecules was monitored in a subgroup of patients with RA undergoing treatment with anti-TNF␣.Results. In addition to higher frequencies of CD28 null T cells, patients with RA had significantly reduced numbers of CD28 and TNFRI molecules on CD4؉,CD28؉ T cells. Normal expression could be restored in vitro by overnight culture, suggesting that CD28 in patients was modulated by exogenous factors. In contrast, treatment with TNF␣ in vitro resulted in further down-regulation. CD28 expression was normalized in patients undergoing TNF␣-neutralizing therapy.Conclusion. Overproduction of TNF␣ in RA induces a global down-regulation of CD28 in CD4؉ T cells and may cause reduced sensitivity to costimulatory signals in T cell responses.

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Section: Discussionmentioning

confidence: 99%

Modulation of CD28 expression with anti–tumor necrosis factor α therapy in rheumatoid arthritis

Bryl¹,

Vallejo²,

Matteson³

et al. 2005

Arthritis & Rheumatism

125

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“…This was a reasonable model given that thymocytes respond to IL-2 in vitro (13,32), IL-2 is expressed in the thymus (10,11,33), and IL-2R␤ is up-regulated on TCR int CD8 low/Ϫ CD4 ϩ thymocytes, a subset that is undergoing selection and is near maturation to CD4 ϩ or CD8 ϩ thymocytes (34). However, negative selection is consistently reported as being normal in the absence of IL-2 or IL-2R␣ (5,19,21,28) or IL-2R␤ (35,36).…”

Section: Il-2 and Central Tolerancementioning

confidence: 99%

IL-2, Regulatory T Cells, and Tolerance

Nelson

2004

The Journal of Immunology

513

378

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IL-2 is a potent T cell growth factor that for many years was assumed to amplify lymphocyte responses in vivo. Accordingly, IL-2 has been used clinically to enhance T cell immunity in patients with AIDS or cancer, and blocking Abs to the IL-2R are used to inhibit T cell responses against transplanted tissues. It was later shown in mice that, unexpectedly, disruption of the IL-2 pathway results in lymphoid hyperplasia and autoimmunity rather than immune deficiency, indicating that the major physiological function of IL-2 is to limit rather than enhance T cell responses. This apparent paradox has recently been resolved with the discovery that IL-2 is critical for the development and peripheral expansion of CD4+CD25+ regulatory T cells, which promote self-tolerance by suppressing T cell responses in vivo. Our new understanding of IL-2 biology prompts a re-evaluation of how best to clinically manipulate this important immunoregulatory pathway.

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“…Consistent with the former hypothesis, preliminary data from our laboratory show that the number of apoptotic cells is decreased in the spleens of IL-2-deficient vs WT hosts treated as described above. We have also previously shown that bound IL-2 promotes activation-induced cell death in vivo using a Rag2 KO model (9).…”

Section: And Ref 9)mentioning

confidence: 76%

“…Although the half-life of bound IL-2 is not known, IL-2 given i.v. into nude mice is detectable for at least 72 h postinfusion (9). IL-2 is found in the perifollicular regions of the spleen and colocalizes with perlecan, a heparan sulfate proteoglycan ( Fig.…”

Section: Resultsmentioning

confidence: 92%

“…To determine whether IL-2 must be retained by heparan sulfate to drive immune responses in vivo, we "reconstituted" the matrices of IL-2-deficient mice with IL-2 by administering the cytokine systemically, as previously described (9). Twenty-four hours after the injection of IL-2, no free IL-2 was detectable in the blood, consistent with its brief half-life (23).…”

Section: And Ref 9)mentioning

confidence: 99%

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Propagation and Control of T Cell Responses by Heparan Sulfate-Bound IL-2

Wrenshall

Platt

Stevens

et al. 2003

The Journal of Immunology

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IL-2, a cytokine produced by T cells, is a key regulator of immune responses and T cell homeostasis. Controlling the availability of IL-2 is consequently of significant import to the immune system. Like other cytokines, IL-2 is thought to function as a soluble agonist, transiently present when secreted in response to appropriate stimuli. In this study, we show that the most salient properties of IL-2, propagation and control of T cell responses, are mediated in vivo by bound and not free cytokine and specifically by heparan sulfate-bound IL-2. These findings necessitate a new look at how IL-2 regulates immune responses and support the notion that the microenvironment plays a determining role in modulating the character of immune responses.

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Regulation of T Cell Deletion by Heparan Sulfate-Bound Interleukin 2.

Cited by 39 publications

References 0 publications

Modulation of CD28 expression with anti–tumor necrosis factor α therapy in rheumatoid arthritis

Modulation of CD28 expression with anti–tumor necrosis factor α therapy in rheumatoid arthritis

IL-2, Regulatory T Cells, and Tolerance

Propagation and Control of T Cell Responses by Heparan Sulfate-Bound IL-2

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