The Subpopulation of CD4+CD25+ Splenocytes That Delays Adoptive Transfer of Diabetes Expresses L-Selectin and High Levels of CCR7

Szanya, Veronika; Ermann, Joerg; Taylor, C. V.; Holness, Claire L.; Fathman, C. Garrison

doi:10.4049/jimmunol.169.5.2461

Cited by 332 publications

(293 citation statements)

References 35 publications

(30 reference statements)

Supporting

Mentioning

273

Contrasting

Unclassified

Order By: Relevance

“…CD62L + and CD62L -populations are similar in that they are both suppressive, although the CD62L + population is a more efficient suppressor population than the CD62L -population [48]. Prior studies by Alyanakian et al [49] reported a central role of CD4 + CD62L + T cells in controlling autoimmune disease in the NOD mouse.…”

Section: Discussionmentioning

confidence: 95%

Interferon regulatory factor‐1 gene deletion decreases glomerulonephritis in MRL/lpr mice

et al. 2006

View full text Add to dashboard Cite

To investigate the role of interferon regulatory factor-1 (IRF-1) in the development of lupus nephritis, IRF-1 -/-genotype mice were bred onto the MRL/lpJfas lpr (MRL/lpr) background. We examined kidney mesangial cell function and disease progression. Endpoints evaluated included inflammatory mediators, autoantibody production, immune complex deposition, renal pathology, T cell subset analysis, and duration of survival. Mesangial cells cultured from IRF-1 -/-mice produced significantly lower levels of nitric oxide and IL-12 but not TNF-a when stimulated with LPS + IFN-c. IRF-1 -/-mice showed less aggravated dermatitis compared to the wild-type mice. Anti-doublestranded DNA production and proteinuria were significantly decreased in IRF-1 -/-mice compared to IRF-1 +/+ mice. IgG and C3 deposition as well as glomerulonephritis were decreased in IRF-1 -/-mice at 26 wk of age compared to the IRF-1 +/+ mice. Splenic CD4 -CD8 -CD44 + T cells were decreased while CD4 + CD25 + T cells were increased in the IRF-1 -/-mice when compared to IRF-1 +/+ mice. Survival rates (ED 50 ) were 22 wk for IRF-1 +/+ mice and 45 wk for IRF-1 -/-mice. These findings suggest an important role of IRF-1 in mediating renal disease in MRL/lpr mice. IntroductionThe etiology of systemic lupus erythematosus remains an enigma although genetic factors influenced by environmental agents appear to trigger the disease. Clearly, B cells, T cells, and macrophages play important roles in the development of lupus pathology [1][2][3].Chronic expression of Th1 cytokines secreted by Th cells is particularly harmful due to their influence on the initiation and promotion of tissue destruction [4,5]. Cytokines, including IFN-c, promote inflammation and provide a positive amplification loop responsible for escalating autoimmune kidney damage [6].MRL/lpr mice develop glomerulonephritis and vasculitis at an early age (4-5 months) [7]. Renal disease is characterized by the early influx of activated T cells and macrophages into the kidney. Activated T cells secrete IFN-c, which induces macrophages to express CSF-1, IL-1b, and TNF-a. Macrophages accumulate in the kidney during inflammation and generate IFN-a, TNF-a, and reactive oxygen species. Locally produced chemokines, particularly monocyte chemoattractant protein (MCP)-1, are also instrumental in attracting and maintaining cellular influx [8] -12 [20]. In the IRF-1 -/-NOD mouse, insulitis and diabetes were decreased accompanied by an increased survival [21]. Additional studies have suggested a role of IRF-1 and IFN-regulated genes in mediating human lupus [22][23][24]. Based on the knowledge that IRF-1 modulates inflammatory mediator production, we sought to determine whether IRF-1 gene deletion alters the severity of lupus nephritis in MRL/lpr mice. Results IRF-1 MRL/lpr mouse phenotypeTo determine the role of IRF-1 in autoimmune disease, IRF-1-knockout mice were backcrossed for eight generations to the MRL/lpr mice. After eight backcrosses, the littermates were intercrossed to yield cohorts for these studies....

show abstract

Section: Discussionmentioning

confidence: 95%

Interferon regulatory factor‐1 gene deletion decreases glomerulonephritis in MRL/lpr mice

et al. 2006

View full text Add to dashboard Cite

show abstract

“…The selective/specific removal of activated T cells expressing surface PD-1 without direct manipulation of Treg minimizes the possibility of altering Treg function. This could represent a potential advantage of PD-1 over CD62L to allow the selection of purer populations of Treg (34,35). In fact, the latter procedure would require the positive selection of CD4 ϩ CD25 ϩ CD62L ϩ by means of specific mAbs.…”

Section: Discussionmentioning

confidence: 99%

Regulated Compartmentalization of Programmed Cell Death-1 Discriminates CD4+CD25+ Resting Regulatory T Cells from Activated T Cells

Raimondi¹,

Shufesky²,

Tokita³

et al. 2006

The Journal of Immunology

160

119

View full text Add to dashboard Cite

More effective discrimination between CD4+CD25+ regulatory T cells (Treg) and activated T cells would significantly improve the current level of purification of Treg and their therapeutic application. We observed that ∼90% of Treg (positive for the nuclear transcription factor Forkhead winged helix protein-3 and able to inhibit naive T cell proliferation) isolated from the spleens or lymph nodes of normal mice did not express significant levels of the inhibitory receptor programmed cell death-1 (PD-1) on their surface, but retained PD-1 intracellularly. An identical phenotype was also identified for human CD4+CD25high T cells isolated from peripheral blood of healthy volunteers. By contrast, activated T cells expressed high levels of surface PD-1 that paralleled up-regulation of CD25 during effector cell expansion. This distinction allowed us to isolate CD4+CD25+PD-1− T cells with suppressive activity from mice immunized with mature allogeneic dendritic cells. Although purification was limited to resting Treg because TCR ligation induced up-regulation of surface PD-1, this strategy nevertheless represents a valuable step toward more definitive characterization of Treg and their improved purification for therapeutic assessment.

show abstract

“…CD25 + CD4 + Treg play a central role in the maintenance of immunological homeostasis and self-tolerance [29]. Treg are by no means homogeneous, but rather can be subdivided into naïve-like subsets, which preferentially recirculate through lymphoid tissues, and effector/memory subsets, which efficiently migrate into peripheral sites and sites of ongoing immune responses [30][31][32][33]. Thus, it is not surprising that Treg display a high HR versatility [31,[34][35][36][37][38][39].…”

mentioning

confidence: 99%

Induction of organ‐selective CD4⁺ regulatory T cell homing

et al. 2007

View full text Add to dashboard Cite

Compelling evidence suggests that Foxp3 + CD25 + CD4 + Treg play a fundamental role in immunoregulation. We have previously demonstrated that Treg have to enter peripheral tissues to suppress ongoing inflammation. However, relatively little is known about how Treg acquire the expression of homing receptors required for tissue-or inflammationspecific migration. Migratory properties of conventional naïve T cells are shaped by the tissue microenvironment and organ-specific dendritic cells during priming. Here, we show that this basic concept also holds true for CD25 + CD4 + Treg: Priming of Treg within peripheral LN led to the expression of selectin ligands, which facilitate migration into inflamed skin, whereas activation within mesenteric LN led to induction of the integrin a 4 b 7 , which is required for migration into mucosal tissues. Furthermore, we could establish in vitro culture systems containing either dendritic cells from mesenteric and peripheral LN, or retinoic acid and IL-12 as polarizing compounds to induce mucosa-and skin-seeking Treg, respectively. Together, our results demonstrate that Treg, similarly to conventional T cells, can be configured with organ-selective homing properties allowing efficient targeting into distinct tissues. IntroductionMigration of T cell subsets to different tissues is determined by the combined expression of adhesion molecules and chemokine receptors (CCR) on the cell surfaces [1][2][3][4]. Among these homing receptors (HR), the integrin a 4 b 7 [5,6] and the chemokine receptor CCR9 [7][8][9] mediate the homing of T cell subsets to GALT such as mesenteric LN (mLN) and Peyer's patches (PP) and to the small intestinal lamina propria and the mucosal epithelium. In contrast, T cell trafficking to the skin is mediated by P-(P-lig) and E-(E-lig) selectin ligands [10,11] as well as .Recently, a number of studies have described that antigen-dependent differentiation of naïve T cells in lymphoid organs leads to the generation of effector T cells exhibiting a capacity to enter peripheral extralymphoid tissues [2]. Effector T cells generated in different lymphoid organs display distinct tissue tropism, which is regulated by an organ-specific induction of adhesion molecules and chemokine receptors during T cell priming [4,[15][16][17][18][19][20][21]. For example, T cells activated in mLN and PP draining the gut acquire high levels of the integrin a 4 b 7 , whereas activation in skin-draining peripheral LN (pLN) results in the upregulation of selectin ligands such as P-lig. Tissuespecific DC have been shown in a number of in vitro and in vivo studies to be involved in the instruction of naïve T cells [4,[17][18][19][20][22][23][24] reported that GALT DC were capable of converting metabolites of dietary vitamin A into retinoic acid (RA), which in turn induced T cell expression of a 4 b 7 and CCR9, leading to the generation of gut-tropic T cells. However, the factors, which are involved in the generation of skin-specific T cell homing in vivo, are largely unknown, although important ...

show abstract

The Subpopulation of CD4+CD25+ Splenocytes That Delays Adoptive Transfer of Diabetes Expresses L-Selectin and High Levels of CCR7

Cited by 332 publications

References 35 publications

Interferon regulatory factor‐1 gene deletion decreases glomerulonephritis in MRL/lpr mice

Interferon regulatory factor‐1 gene deletion decreases glomerulonephritis in MRL/lpr mice

Regulated Compartmentalization of Programmed Cell Death-1 Discriminates CD4+CD25+ Resting Regulatory T Cells from Activated T Cells

Induction of organ‐selective CD4⁺ regulatory T cell homing

Contact Info

Product

Resources

About

The Subpopulation of CD4+CD25+ Splenocytes That Delays Adoptive Transfer of Diabetes Expresses L-Selectin and High Levels of CCR7

Cited by 332 publications

References 35 publications

Interferon regulatory factor‐1 gene deletion decreases glomerulonephritis in MRL/lpr mice

Interferon regulatory factor‐1 gene deletion decreases glomerulonephritis in MRL/lpr mice

Regulated Compartmentalization of Programmed Cell Death-1 Discriminates CD4+CD25+ Resting Regulatory T Cells from Activated T Cells

Induction of organ‐selective CD4+ regulatory T cell homing

Contact Info

Product

Resources

About

Induction of organ‐selective CD4⁺ regulatory T cell homing