Dynamic changes in CD4+ CD25+ high T cell apoptosis after the diagnosis of type 1 diabetes

Glisic-Milosavljevic, Sanja; Wang, T.; Koppen, Marilyn; Kramer, Joanna; Ehlenbach, S.J.; Waukau, Jill; Jailwala, Parthav; Jana, Swapan Kumar; Alemzadeh, Ramin; Ghosh, Soumitra

doi:10.1111/j.1365-2249.2007.03475.x

Cited by 30 publications

(26 citation statements)

References 22 publications

(24 reference statements)

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“…This result was seen in earlier studies. 19,28 However, despite this, there was still a significant impact of HLA DQ risk status on variation of CD4 þ CD25 þ high T-cell apoptosis. Association of the HLA region to T1D has been described in many studies.…”

Section: Discussionmentioning

confidence: 99%

Genetic association of HLA DQB1 with CD4+CD25+high T-cell apoptosis in type 1 diabetes

et al. 2009

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Type 1 diabetes (T1D) has a strong genetic component and the major locus lies in the HLA DQB1 region. We found earlier an increased apoptosis with decreased viability and function of the CD4 þ CD25 þ high T-cell subset (Treg) in human subjects with recent-onset T1D and in multiple autoantibody-positive, high at-risk individuals. Tregs normally inhibit or delay onset of T1D in animal models and increased Treg apoptosis could bring on or accelerate disease from effector T-cell-mediated destruction of insulin-producing beta cells. In this study, we test the hypothesis that HLA DQB1 genotypes are associated with increased CD4 þ CD25 þ high T-cell apoptosis. HLA DQ-based genetic risk status was significantly associated with CD4 þ CD25 þ high T-cell apoptosis, after adjustment for age, gender and phenotypic status (n ¼ 83, F ¼ 4.04 (d.f. ¼ 3), P ¼ 0.01). Unaffected, autoantibody-negative high risk HLA DQB1 control subjects showed increased CD4 þ CD25 þ high apoptosis levels compared with low risk HLA DQB1 control subjects (n ¼ 26, P ¼ 0.002), confirming that the association precedes disease. The association of specific HLA DQB1 genotypes with Treg apoptosis was also tested, showing significance for HLA DQB1*0302, DQB1*0201 and HLA DQB1*0602 alleles. Our study shows an association of HLA DQB1 genotypes with CD4 þ CD25 þ high T-cell apoptosis, which implicates CD4 þ CD25 þ high T-cell apoptosis as a new intermediate trait for T1D.

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Section: Discussionmentioning

confidence: 99%

Genetic association of HLA DQB1 with CD4+CD25+high T-cell apoptosis in type 1 diabetes

et al. 2009

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“…IL-2 is the primary T cell growth factor which binds to its cognate receptor CD25 on T cells to initiate T cell proliferation. CD25 has been identified as a therapeutic target in conditions such as cancer [31,32] autoimmunity [33] and asthma susceptibility [34] and levels or soluble CD25 are being evaluated for their diagnostic potential [35,36]. …”

Section: Discussionmentioning

confidence: 99%

Bromelain treatment reduces CD25 expression on activated CD4+ T cells in vitro

Secor

Singh

Guernsey

et al. 2009

International Immunopharmacology

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Bromelain (Br), an extract from pineapple stem with cysteine protease activity, exerts anti-inflammatory effects in a number of inflammatory models. We have previously shown that Br treatment decreased activated CD4+ T cells and has a therapeutic role in an ovalbumin-induced murine model of allergic airway disease. The current study was designed to determine the effect of Br on CD4+ T cell activation, specifically the expression of CD25 in vitro. CD25 is up regulated upon T cell activation, found as a soluble fraction (sCD25) and is a therapeutic target in inflammation, autoimmunity and allergy. Br treatment of anti-CD3 stimulated CD4+ T cells reduced CD25 expression in a dose and time dependent manner. This reduction of CD25 was dependent on the proteolytic action of Br as the addition of E64 (a cysteine protease inhibitor) abrogated this response. The concentration of sCD25 was increased in supernatants of Br treated activated CD4+ T cells as compared to control cells, suggesting that Br proteolytically cleaved cell-surface CD25. This novel mechanism of action identifies how Br may exert its therapeutic benefits in inflammatory conditions.

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“…Taken together, we have provided additional understanding of the mechanisms for the generation of iTreg cells. Since in autoimmune diseases, nTreg pathways are probably suboptimal [49,50] and nTreg may also be prone to apoptosis [51,52], it is clear that an added strategy with well-understood pathways for iTreg generation will be helpful to our therapeutic arsenal. .…”

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The role of NF‐κB and Smad3 in TGF‐β‐mediated Foxp3 expression

et al. 2009

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The transcription factor Foxp3 is essential for the development of functional, natural Treg (nTreg), which plays a prominent role in self-tolerance. Suppressive Foxp3 + Treg cells can be generated from naïve T cells ex vivo, following TCR and TGF-b1 stimulations. However, the molecular contributions from the different arms of these pathways leading to Foxp3 expression are not fully understood. TGF-b1-activated Smad3 plays a major role in the expression of Foxp3, since TGF-b1-induced-Treg generation from Smad3 À/À mice is markedly reduced and abolished by inactivating Smad2. In the TCR pathway, deletion of Bcl10, which activates NF-jB, markedly reduces both IL-2 and Foxp3 production. However, partial rescue of Foxp3 expression occurs on addition of exogenous IL-2. TGF-b1 significantly attenuates NF-jB binding to the Foxp3 promoter, while inducing Foxp3 expression. Furthermore, deletion of p50, a NF-jB subunit, results in increased Foxp3 expression despite a decline in the IL-2 production. We posit several TCR-NF-jB pathways, some increasing (Bcl10-IL-2-Foxp3) while others decreasing (p50-Foxp3) Foxp3 expression, with the former predominating. A better understanding of Foxp3 regulation could be useful in dissecting the cause of Treg dysfunction in several autoimmune diseases and for generating more potent TGF-b1-induced-Treg cells for therapeutic purposes. There are reports documenting a reduction in the number or function of Treg cells in patients with numerous autoimmune diseases, including diabetes, rheumatoid arthritis, psoriasis, myasthenia gravis or sarcoidosis [12][13][14][15]. Thus, one possible way for restoration of self-tolerance in these patients could be by the infusion of Treg cells having an increased ability to control ongoing autoimmune destruction. Due to the limited availability of nTreg cells, in vitro generated iTreg cells may serve as an alternative source of Treg cells for therapeutic purposes. There is strong evidence that these Foxp3 + iTreg cells can prevent/delay the development of Type 1 Diabetes in the NOD mice [16,17]. Hence, the regulation of Foxp3 expression during iTreg generation is of considerable interest. Relatively little is known about the regulation of Foxp3 in the periphery. The essential roles of IL-2, TGF-b and TCR signaling in iTreg generation have been established [11,[18][19][20]. However, it is unclear which particular arms in each of these pathways are important in FoxP3 regulation. TGF-b1 is a pluripotent cytokine that has pronounced effects on T-cell-mediated immune suppression as well as on the control of autoimmunity. The binding of TGF-b1 to its receptor complex activates the intracellular kinase domain of TGF-bRII, which leads to the phosphorylation and activation of Smad2, Smad3 and Smad4 as well as non-Smad proteins (Smad-independent pathway) [21]. After forming a heterodimer with phosphorylated Smad4, activated Smad2 and Smad3 translocate to the nucleus where they regulate TGF-b1-dependent gene expression. The generation of nTreg cells from the thymus of TGF...

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Dynamic changes in CD4+ CD25+ high T cell apoptosis after the diagnosis of type 1 diabetes

Cited by 30 publications

References 22 publications

Genetic association of HLA DQB1 with CD4+CD25+high T-cell apoptosis in type 1 diabetes

Genetic association of HLA DQB1 with CD4+CD25+high T-cell apoptosis in type 1 diabetes

Bromelain treatment reduces CD25 expression on activated CD4+ T cells in vitro

The role of NF‐κB and Smad3 in TGF‐β‐mediated Foxp3 expression

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