IL-21 Limits Peripheral Lymphocyte Numbers through T Cell Homeostatic Mechanisms

Datta, Shrimati; Sarvetnick, Nora

doi:10.1371/journal.pone.0003118

Cited by 48 publications

(65 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…IL-21 is necessary for the development of diabetes in the NOD mouse (23)(24)(25), but a number of important studies argue that decreased expression of IL-2 explains Idd3 (14,15,31). Our findings resonate with a critical role for IL-21 in T1D pathogenesis, but do not formally discount a role for IL-2.…”

Section: Discussioncontrasting

confidence: 55%

“…IL-21 is produced by activated CD4 ϩ T cells and NK T cells, and can deliver a costimulatory signal to lymphocytes that affects their proliferation, differentiation, and survival in response to antigen (19)(20)(21). Consistent with its actions on lymphocyte populations, IL-21 has been shown to have an essential role in an array of conditions involving the destruction of self-tissues (20,(22)(23)(24). We have previously shown that NOD mice exhibited elevated levels of IL-21 (26), and a number of recent studies of NOD mice made genetically deficient in the IL-21R demonstrate that IL-21 is necessary for the development of T1D (23)(24)(25).…”

mentioning

confidence: 99%

“…In contrast, they are also known to support the generation of lymphocyte subsets with opposing actions. This complexity is illustrated by the finding that a homozygous deficiency in Il21r prevents the onset of T1D in the NOD mouse, whereas a loss of one allele of Il2 increases disease incidence (15,(23)(24)(25). IL2 and Il21 are adjacent genes on chromosome 3 in mice, and the analogous locus exists on chromosome 4 in humans.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Loss of parity between IL-2 and IL-21 in the NOD Idd3 locus

McGuire

Vogelzang

Hill

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

IL-2 and IL-21 are two cytokines with great potential to affect autoimmune infiltration of nonlymphoid tissue, and are contained within the strongest non-MHC-linked locus for type 1 diabetes (T1D) susceptibility on the nonobese diabetic (NOD) mouse (Idd3). IL-21 is necessary for the development of diabetes in the NOD mouse, but a number of important studies argue that decreased expression of IL-2 explains Idd3. In this study, we demonstrate that the amount of IL-21, but not IL-2, correlated with T1D incidence. During our analyses of the IL-2/IL-21 interval, we found that mice segregate into one of two distinct expression profiles. In the first group, which includes the C57BL/6 strain, both Il2 and Il21 were expressed at low levels. In the other group, which includes the NOD strain, Il2 and Il21 were both highly expressed. However, because NOD IL-2 mRNA was relatively unstable, IL-2 production was remarkably similar between strains. The increased production of IL-21 in NOD mice was found to result from two single nucleotide polymorphisms within the distal promoter region that conferred increased binding affinity for the transcription factor Sp1. Our findings indicate that a loss of locus parity after decreased IL-2 mRNA stability ensures that the high-expressing IL-21 allele persists in nature and provides a basis for autoimmunity. type 1 diabetes ͉ cytokines ͉ transcription factor ͉ allele ͉ promoter

show abstract

Section: Discussioncontrasting

confidence: 55%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Loss of parity between IL-2 and IL-21 in the NOD Idd3 locus

McGuire

Vogelzang

Hill

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…In humans several autoimmune diseases including type 1 diabetes, rheumatoid arthritis and Crohns have been associated with lymphopenia 42,43 . Moreover, mild lymphopenia and compensatory IL-21-dependent homoeostatic proliferation in nonobese diabetic mice that are prone to the development of autoimmunity have been reported to promote type 1 diabetes 44,45 . Similarly, deregulated regulatory T-cell expansion in lymphopenic nonobese diabetic hosts contributes to the development of type 1 diabetes 46 , whereas IL-7-mediated T-cell LIP in lupus or type 1 diabetes predisposed mice enhances their progression to disease 47,48 .…”

Section: Discussionmentioning

confidence: 99%

PTPN2 attenuates T-cell lymphopenia-induced proliferation

2014

View full text Add to dashboard Cite

When the peripheral T-cell pool is depleted, T cells undergo homoeostatic expansion. This expansion is reliant on the recognition of self-antigens and/or cytokines, in particular interleukin-7. The T cell-intrinsic mechanisms that prevent excessive homoeostatic T-cell responses and consequent overt autoreactivity remain poorly defined. Here we show that protein tyrosine phosphatase N2 (PTPN2) is elevated in naive T cells leaving the thymus to restrict homoeostatic T-cell proliferation and prevent excess responses to self-antigens in the periphery. PTPN2-deficient CD8 þ T cells undergo rapid lymphopenia-induced proliferation (LIP) when transferred into lymphopenic hosts and acquire the characteristics of antigenexperienced effector T cells. The enhanced LIP is attributed to elevated T-cell receptordependent, but not interleukin-7-dependent responses, results in a skewed T-cell receptor repertoire and the development of autoimmunity. Our results identify a major mechanism by which homoeostatic T-cell responses are tuned to prevent the development of autoimmune and inflammatory disorders.

show abstract

“…In a murine model of autoimmune colitis, IL-6-dependent spontaneous proliferation of colitogenic CD8 + T cells and their conversion to IL-17-producing effector cells underlie the pathogenic process (7). In the NOD mouse model, genetic ablation of IL21Ra abrogated the development of autoimmune diabetes (8)(9)(10). In a mouse model of autoimmune diabetes, IL-7 promoted the activation of autoreactive CD8 T cells by facilitating CD4 T cells to provide help (11).…”

mentioning

confidence: 99%

Exposure to IL-15 and IL-21 Enables Autoreactive CD8 T Cells To Respond to Weak Antigens and Cause Disease in a Mouse Model of Autoimmune Diabetes

Ramanathan

Dubois

Chen

et al. 2011

The Journal of Immunology

View full text Add to dashboard Cite

Autoreactive CD8+ T lymphocytes play a key role in the pathogenesis of several autoimmune diseases. It is not yet well understood how autoreactive CD8+ T cells, which express TCRs with low reactivity toward self-Ags, gain the ability to respond to autoantigens to cause disease. Previously, we have shown that prior stimulation of CD8+ T cells with synergistic combinations of cytokines produced by the innate immune response, such as IL-21 and IL-15, induces Ag-independent proliferation. Such “cytokine-primed” CD8 T cells displayed increased responsiveness to limiting quantities of the cognate Ag. In this paper, we report that prior stimulation with IL-15 and IL-21 also enables CD8+ T cells to respond to weakly agonistic TCR ligands, resulting in proliferation, cytokine secretion, and cytolytic activity. Using a transgenic mouse model of autoimmune diabetes, we show that cytokine-primed autoreactive CD8+ T cells induce disease following stimulation by weak TCR ligands, but their diabetogenic potential is dependent on continuous availability of IL-15 in vivo. These findings suggest that inflammatory cytokines could facilitate the triggering of autoreactive CD8+ T cells by weak autoantigens, and this mechanism may have important implications for autoimmune diseases associated with microbial infections and chronic inflammation.

show abstract

IL-21 Limits Peripheral Lymphocyte Numbers through T Cell Homeostatic Mechanisms

Cited by 48 publications

References 64 publications

Loss of parity between IL-2 and IL-21 in the NOD Idd3 locus

Loss of parity between IL-2 and IL-21 in the NOD Idd3 locus

PTPN2 attenuates T-cell lymphopenia-induced proliferation

Exposure to IL-15 and IL-21 Enables Autoreactive CD8 T Cells To Respond to Weak Antigens and Cause Disease in a Mouse Model of Autoimmune Diabetes

Contact Info

Product

Resources

About