Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells

Guimond, Martin; Veenstra, Rachelle G.; Grindler, David J.; Zhang, Hua; Cui, Yongzhi; Murphy, Ryan; Kim, Su Young; Na, Risu; Hennighausen, Lothar; Kurtuluş, Sema; Erman, Batu; Matzinger, Polly; Merchant, Melinda S.; Mackall, Crystal L.

doi:10.1038/ni.1695

Cited by 194 publications

(210 citation statements)

References 51 publications

(62 reference statements)

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“…Thus, although regulatory CD4 + T cells express very low surface levels of IL-7R, they are still able to integrate IL-7-mediated signals. However, the concentrations of IL-7 used in in vitro assays (10-50 ng/ml) are higher than the concentrations reached, in vivo, in a lymphopenic environment [∼50 pg/ml in the serum of T cell-deficient mice (19)]. Interestingly, after injection into lymphopenic recipient mice expressing or not expressing MHC class II molecules, IL-7R surface levels on conventional CD4 + T cells decreased to the levels observed on regulatory CD4 + T cells but not to lower levels.…”

Section: Regulatory Cd4 + T Cells Receive Help From Conventional Cd4 mentioning

confidence: 99%

“…1A, 1B). This slow and limited proliferation of naive CD4 + T cells is known to result directly from the greater availability of IL-7 in lymphopenic environments (19,32,33). In contrast, although regulatory CD4 + T cells (CFSE + Foxp3 + CD4 + ) were able to proliferate even more strongly than were their conventional CD4 + T cell counterparts after transfer into lymphopenic MHC class II-expressing recipient mice, this proliferating capacity appeared to be strongly compromised in mice lacking the expression of MHC class II molecules (Fig.…”

Section: Il-7 Alone Does Not Drive Homeostatic Proliferation Of Regulmentioning

confidence: 99%

“…IL-7 is not required for this process, which is called "spontaneous proliferation" (18). On the other hand, the vast majority of injected naive T cells cycles slowly in response to the great availability of IL-7 in lymphopenic environments (19). TCR signaling can also synergize with IL-7 to enhance this latter process, which is called "homeostatic T cell proliferation" (18).…”

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confidence: 99%

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IL-2 and IL-7 Determine the Homeostatic Balance between the Regulatory and Conventional CD4+ T Cell Compartments during Peripheral T Cell Reconstitution

Campion

Pommier²,

Delpoux³

et al. 2012

The Journal of Immunology

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Work over the last decades has led to the identification of the factors that influence the survival and homeostasis of conventional T cells. IL-7 and TCR signaling promote the survival of naive CD4+ and CD8+ T cells in lymphoreplete mice and their proliferation in a lymphopenic environment, whereas survival and homeostatic proliferation of memory CD4+ and CD8+ T cells crucially depend on a combination of IL-7 and IL-15. In contrast, there is little information regarding the factors driving the proliferation of regulatory CD4+ T cells in response to lymphopenia. In this study, we investigated whether regulatory CD4+ T cell proliferation in response to lymphopenia was guided by classical homeostatic resources, such as IL-2, IL-7, or TCR–MHC interactions. Altogether, our data suggest that, although homeostatic proliferation of conventional naive CD4+ T cells is closely related to IL-7 levels, the proliferation of regulatory CD4+ T cells in response to lymphopenia appears to be primarily controlled by IL-2. The capacity of IL-7 to augment conventional T cell proliferation with minimal concomitant regulatory T cell expansion may be clinically exploitable in the treatment of patients with lymphopenia, especially in the case of chronic viral diseases or cancer immunotherapy.

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Section: Regulatory Cd4 + T Cells Receive Help From Conventional Cd4 mentioning

confidence: 99%

Section: Il-7 Alone Does Not Drive Homeostatic Proliferation Of Regulmentioning

confidence: 99%

mentioning

confidence: 99%

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IL-2 and IL-7 Determine the Homeostatic Balance between the Regulatory and Conventional CD4+ T Cell Compartments during Peripheral T Cell Reconstitution

Campion

Pommier²,

Delpoux³

et al. 2012

The Journal of Immunology

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“…Unlike activation cytokines, where cytokine production and receptor expression mediate transient effects following immune activation, tonic IL-7 signals are continuously delivered to nearly all T cells, and IL-7 provides continuous survival signals to naïve T cells (1,2). Under normal conditions, IL-7 is a limited resource (3), but diminished IL-7 consumption in lymphopenic hosts leads to elevated IL-7 levels that enhance proliferative responses to weak self-antigens (4,5), thus driving homeostatic proliferation (6). Proliferative responses to self-antigens can also be induced by pharmacologic dosing of IL-7 in lymphoreplete hosts (7,8), and increases in IL-7 availability, induced by lymphopenia (9), pharmacologic administration (10), or constitutive overexpression in IL-7 transgenic mice (11) predispose to autoimmune disease.…”

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confidence: 99%

Soluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity

Lundström

Highfill

Walsh

et al. 2013

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

126

153

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Human soluble interleukin-7 receptor (sIL7R)α circulates in high molar excess compared with IL-7, but its biology remains unclear. We demonstrate that sIL7Rα has moderate affinity for IL-7 but does not bind thymic stromal lymphopoietin. Functionally, sIL7Rα competes with cell-associated IL-7 receptor to diminish excessive IL-7 consumption and, thus, enhances the bioactivity of IL-7 when the cytokine is limited, as it is presumed to be in vivo. IL-7 signaling in the presence of sIL7Rα also diminishes expression of CD95 and suppressor of cytokine signaling 1, both regulatory molecules. Murine models confirm diminished consumption of IL-7 in the presence of sIL7Rα and also demonstrate a potentiating effect of sIL7Rα on IL-7-mediated homeostatic expansion and experimental autoimmune encephalomyelitis exacerbation. In multiple sclerosis and several other autoimmune diseases, IL7R genotype influences susceptibility. We measured increased sIL7Rα levels, as well as increased IL-7 levels, in multiple sclerosis patients with the predisposing IL7R genotype, consistent with diminished IL-7 consumption in vivo. This work demonstrates that sIL7Rα potentiates IL-7 bioactivity and provides a basis to explain the increased risk of autoimmunity observed in individuals with genotype-induced elevations of sIL7Rα.immunology | soluble receptors | tolerance

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“…CD45 does not affect IL-7 transcripts in DCs, and the rescue of LIP by CD45 + CD11c + DCs does not restore IL-7 levels IL-7 is produced mainly by stromal cells, but a couple of reports suggest that DCs can also produce IL-7 transcripts (34,35). To check the IL-7 levels in DCs, we measured IL-7 mRNA levels by QPCR in BMDCs and ex vivo splenic DCs.…”

Section: Il-15/il15ra Levels Are Not Defective In Cd45ko Dcsmentioning

confidence: 99%

Innate Immune Cell CD45 Regulates Lymphopenia-Induced T Cell Proliferation

Saunders

Shim

Johnson

2014

The Journal of Immunology

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The leukocyte-specific tyrosine phosphatase, CD45, severely impacts T cell development and activation by modulating TCR signaling. CD45-deficient (CD45KO) mice have reduced peripheral T cell numbers where CD8 T cells are underrepresented. In this article, we show that CD45KO mice are unable to support efficient homeostatic proliferation, affecting CD8 T cells more than CD4 T cells. Using CD45-RAG1 double-deficient (45RAGKO) mice, we show that lymphopenia-induced proliferation (LIP) of CD45-sufficient T cells is defective in a host environment lacking CD45 on innate immune cells. We identify two deficiencies in the 45RAGKO mice that affect LIP. One involves CD11c+ cells and the second the production of IL-7 by lymphoid stromal cells. CD45KO dendritic cells were not defective in foreign Ag–induced T cell proliferation, yet CD45KO CD11c+ cells were unable to rescue the spontaneous LIP in the 45RAGKO mice. This was in contrast with the CD45-sufficient CD11c+ cells that partially rescued this spontaneous proliferation and did so without affecting IL-7 levels. The absence of CD45 also led to reduced IL-7 production by lymphoid stromal cells, suggesting an indirect effect of CD45 on innate immune cells in influencing IL-7 production by lymphoid stromal cells. These findings demonstrate a novel role for CD45 on innate immune cells in promoting lymphopenia-induced T cell proliferation and suggest that innate immune cells may communicate with stromal cells to regulate IL-7 production.

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Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells

Cited by 194 publications

References 51 publications

IL-2 and IL-7 Determine the Homeostatic Balance between the Regulatory and Conventional CD4+ T Cell Compartments during Peripheral T Cell Reconstitution

IL-2 and IL-7 Determine the Homeostatic Balance between the Regulatory and Conventional CD4+ T Cell Compartments during Peripheral T Cell Reconstitution

Soluble IL7Rα potentiates IL-7 bioactivity and promotes autoimmunity

Innate Immune Cell CD45 Regulates Lymphopenia-Induced T Cell Proliferation

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