Dendritic cell-derived IL-2 production is regulated by IL-15 in humans and in mice

Feau, Sonia; Facchinetti, Valeria; Granucci, Francesca; Citterio, Stefania; Jarrossay, David; Seresini, Samantha; Protti, Maria Pia; Lanzavecchia, Antonio; Ricciardi‐Castagnoli, Paola

doi:10.1182/blood-2004-03-1059

Cited by 87 publications

(67 citation statements)

References 33 publications

(39 reference statements)

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“…As recently reported for human DC [34], we found that the addition of IL-4 during DC differentiation completely block the ability of mouse BMDC to produce IL-2 in response to LPS. This block is irreversible since IL-4 withdrawal during stimulation does not restore DC responsiveness and the addition of IL-4 to BMDC differentiated in the presence of the sole GM-CSF strongly reduces IL-2 production upon microbial stimulation (data not shown).…”

Section: Discussionsupporting

confidence: 88%

CD40/CD40L interaction regulates CD4⁺CD25⁺ T reg homeostasis through dendritic cell‐produced IL‐2

et al. 2005

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CD4 + CD25 + regulatory T cells (T reg) development and homeostasis require IL-2 and costimulation through same TNF-receptor family members. CD40KO mice have reduced number of T reg in peripheral blood, thymus and spleen. Herein we show that naive T reg express low basal level of CD40L that is upregulated upon TCR-triggered mediated activation. Treatment of wt mice with Ab blocking CD40/CD40L interaction results in a fast decrease in T reg number that rapidly recovers upon Ab withdrawal. CFSE-labeled T reg from wt mice injected into CD40KO, but not wild-type (wt) mice, showed reduced survival and proliferation in homeostatic setting. In vitro, dendritic cells from CD40KO mice but not wt mice produce diminished amount of IL-2 upon T reg encounter and are impaired in expanding T reg, a defect corrected by the addition of rIL-2. Accordingly, four daily IL-2 administrations to CD40KO mice normalize T reg number by promoting both their survival and homeostatic proliferation. Such IL-2 effect is transient since T reg number returns to the low constitutive level described in CD40KO mice within 5 days upon IL-2 withdrawal thus suggesting that IL-2 is persistently needed to assure T reg homeostasis.

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Section: Discussionsupporting

confidence: 88%

CD40/CD40L interaction regulates CD4⁺CD25⁺ T reg homeostasis through dendritic cell‐produced IL‐2

et al. 2005

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“…The reasons for using a mouse model to study alterations in DC functional activation on acute exposure to PM species included the notion that airway DC are the key initiators of the allergic innate immune response in the lung in murine models of asthma [12,[33][34][35] . We have compared PM species known to have adverse health effects in human subjects including ambient environmental (APM) and emission source (DEP) pollutant particles with commercially available carbon black particles (CBP) and engineered silver nanoparticles (AgP) in vivo.…”

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confidence: 99%

Activation of Pulmonary Dendritic Cells and Th2-Type Inflammatory Responses on Instillation of Engineered, Environmental Diesel Emission Source or Ambient Air Pollutant Particles in vivo

et al. 2010

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The biological effects of acute particulate air pollution exposure in host innate immunity remain obscure and have relied largely on in vitro models. We hypothesized that single acute exposure to ambient or engineered particulate matter (PM) in the absence of other secondary stimuli would activate lung dendritic cells (DC) in vivo and provide information on the early immunological events of PM exposure and DC activation in a mouse model naïve to prior PM exposure. Activation of purified lung DC was studied following oropharyngeal instillation of ambient particulate matter (APM). We compared the effects of APM exposure with that of diesel-enriched PM (DEP), carbon black particles (CBP) and silver nanoparticles (AgP). We found that PM species induced variable cellular infiltration in the lungs and only APM exposure induced eosinophilic infiltration. Both APM and DEP activated pulmonary DC and promoted a Th2-type cytokine response from naïve CD4+ T cells ex vivo. Cultures of primary peribronchial lymph node cells from mice exposed to APM and DEP also displayed a Th2-type immune response ex vivo. We conclude that exposure of the lower airway to various PM species induces differential immunological responses and immunomodulation of DC subsets. Environmental APM and DEP activated DC in vivo and provoked a Th2 response ex vivo. By contrast, CBP and AgP induced altered lung tissue barrier integrity but failed to stimulate CD4+ T cells as effectively. Our work suggests that respirable pollutants activate the innate immune response with enhanced DC activation, pulmonary inflammation and Th2-immune responsiveness.

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“…It remains to be determined as to whether the T cells upon stimulation by the DC [51], or DC themselves, or both of the cell types together, could be the direct source of IL-2. In addition, DC can also produce IL-15 [48,49,54], but whether or not and how this cytokine is involved in Treg induction is still to be clarified [53,55]. We showed that, in contrast to the MRL/+ Treg, MRL/lpr Treg were unresponsive to exogenous IL-15 in the presence of either MRL/+ or MRL/lpr DC.…”

Section: Discussionmentioning

confidence: 80%

Immunological mechanisms and clinical implications of regulatory T cell deficiency in a systemic autoimmune disorder: Roles of IL‐2 versus IL‐15

et al. 2008

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Regulatory T cell deficiency is evident in patients with lupus, but the casual relationship and underlying mechanism leading to Treg deficiency are unclear. We analyzed the Treg profile, induction and functions of Treg in a lupus mouse model. A characteristic agedependent biphasic change of Treg frequency was observed in the MRL/lpr mice, which developed a spontaneous lupus-like disease. After an early increase, Treg frequency in the peripheral lymphoid organs rapidly declined with age. Functionally, Treg from both young and old MRL/lpr mice were fully competent in suppressing the wild-type MRL/+ T effector cell (Teff) responses. Adoptive transfer of MRL/+ Treg markedly suppressed clinical disease in the MRL/lpr mice. We demonstrated that the reduced Treg frequency was a result of insufficient peripheral Treg expansion due to defective MRL/lpr Teff in IL-2 production, and the associated defects in dendritic cells, which could be fully restored by exogenous IL-2. In the absence of IL-2, MRL/lpr Teff but not MRL/lpr Treg were highly responsive to IL-15 and could expand rapidly due to enhanced IL-15R expression and IL-15 synthesis. These findings thus provide a clear causal relationship and immunological mechanism underlying Treg deficiency and systemic autoimmunity.

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Dendritic cell-derived IL-2 production is regulated by IL-15 in humans and in mice

Cited by 87 publications

References 33 publications

CD40/CD40L interaction regulates CD4⁺CD25⁺ T reg homeostasis through dendritic cell‐produced IL‐2

CD40/CD40L interaction regulates CD4⁺CD25⁺ T reg homeostasis through dendritic cell‐produced IL‐2

Activation of Pulmonary Dendritic Cells and Th2-Type Inflammatory Responses on Instillation of Engineered, Environmental Diesel Emission Source or Ambient Air Pollutant Particles in vivo

Immunological mechanisms and clinical implications of regulatory T cell deficiency in a systemic autoimmune disorder: Roles of IL‐2 versus IL‐15

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Dendritic cell-derived IL-2 production is regulated by IL-15 in humans and in mice

Cited by 87 publications

References 33 publications

CD40/CD40L interaction regulates CD4+CD25+ T reg homeostasis through dendritic cell‐produced IL‐2

CD40/CD40L interaction regulates CD4+CD25+ T reg homeostasis through dendritic cell‐produced IL‐2

Activation of Pulmonary Dendritic Cells and Th2-Type Inflammatory Responses on Instillation of Engineered, Environmental Diesel Emission Source or Ambient Air Pollutant Particles in vivo

Immunological mechanisms and clinical implications of regulatory T cell deficiency in a systemic autoimmune disorder: Roles of IL‐2 versus IL‐15

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CD40/CD40L interaction regulates CD4⁺CD25⁺ T reg homeostasis through dendritic cell‐produced IL‐2

CD40/CD40L interaction regulates CD4⁺CD25⁺ T reg homeostasis through dendritic cell‐produced IL‐2