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1.
Allergy ; 2024 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-39324367

RESUMEN

Allergic disease is caused by the activation of allergen-specific CD4+ type-2 T follicular helper cells (Tfh2) and T helper 2 (Th2) effector cells that secrete the cytokines IL-4, IL-5, IL-9, and IL-13 upon allergen encounter, thereby inducing IgE production by B cells and tissue inflammation. While it is accepted that the priming and differentiation of naïve CD4+ T cells into Th2 requires allergen presentation by type 2 dendritic cells (DC2s), the underlying signals remain unidentified. In this review we focus on the interaction between allergen-presenting DC2s and naïve CD4+ T cells in lymph node (LN), and the potential mechanisms by which DC2s might instruct Th2 differentiation. We outline recent advances in characterizing DC2 development and heterogeneity. We review mechanisms of allergen sensing and current proposed mechanisms of Th2 differentiation, with specific consideration of the role of DC2s and how they might contribute to each mechanism. Finally, we assess recent publications reporting a detailed analysis of DC-T cell interactions in LNs and how they support Th2 differentiation. Together, these studies are starting to shape our understanding of this key initial step of the allergic immune response.

2.
Proc Natl Acad Sci U S A ; 115(5): 1033-1038, 2018 01 30.
Artículo en Inglés | MEDLINE | ID: mdl-29339496

RESUMEN

T helper 2 (Th2) cells are pivotal in the development of allergy. Allergen exposure primes IL-4+ Th2 cells in lymph node, but production of effector cytokines including IL-5 and IL-13 is thought to require additional signals from antigen and the environment. Here we report that a substantial proportion of naive CD4+ T cells in spleen and lymph node express receptors for the epithelium-derived inflammatory cytokine thymic stromal lymphopoietin (TSLP). Culture of naive CD4+ T cells in anti-(a)CD3, aCD28, and TSLP-supplemented Th2 conditions enabled the development of a unique population of IL-13-single positive (IL-13-SP) CD4+ T cells; TSLP and Th2 conditions were both required for their development. Sorting experiments revealed that IL-13-SP Th2 cells originated from IL-4-negative precursors and coexpressed transcripts for the Th2 cytokines IL-5 and IL-9. In vivo, high TSLP levels acted directly on CD4+ T cells to induce the development of IL-13-SP and IL-4+IL-13+ double-positive populations in lymph node. These cells were phenotypically similar to Th2 effector cells and were CXCR5lowPD1low and expressed low levels of Bcl6 and Il21 transcripts and high levels of Gata3, Il3, and Il5 Our findings suggest a role of TSLP in directly promoting Th2 cell effector function and support the notion of TSLP as a key driver of Th2 inflammation.


Asunto(s)
Citocinas/inmunología , Células Th2/inmunología , Traslado Adoptivo , Animales , Diferenciación Celular/inmunología , Citocinas/deficiencia , Citocinas/genética , Femenino , Humanos , Interleucina-13/genética , Interleucina-13/metabolismo , Interleucina-4/genética , Interleucina-4/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Receptores de Interleucina-7/metabolismo , Células Th2/clasificación , Células Th2/citología , Linfopoyetina del Estroma Tímico
3.
J Immunol ; 193(5): 2504-11, 2014 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-25057004

RESUMEN

The cytokine thymic stromal lymphopoietin (TSLP) is produced by epithelia exposed to the contact sensitizer dibutyl phthalate (DBP), and it is critical for the induction of Th2 immune responses by DBP-FITC. TSLP is thought to act on dendritic cells (DC), but the precise DC subsets involved in the response to TSLP remain to be fully characterized. In this study we show that a subset of CD326(lo)CD103(lo)CD11b(lo) dermal DC, which we termed "triple-negative (TN) DC," is highly responsive to TSLP. In DBP-FITC-treated mice, TN DC upregulated expression of CD86 and rapidly migrated to the draining lymph node to become the most abundant skin-derived DC subset at 24 and 48 h after sensitization. None of these responses was observed in TSLPR-deficient mice. In contrast, TN DC numbers were not increased after treatment with the allergen house dust mite or the bacteria Escherichia coli and bacillus Calmette-Guérin, which increased other DC subsets. In vivo, treatment with rTSLP preferentially increased the numbers of TN DC in lymph nodes. In vitro, TN DC responded to rTSLP treatment with a higher level of STAT5 phosphorylation compared with other skin-derived DC subsets. The TN DC subset shared the morphology, phenotype, and developmental requirements of conventional DC, depending on FLT3 expression for their optimal development from bone marrow precursors, and CCR7 for migration to the draining lymph node. Thus, TN DC represent a dermal DC subset that should be considered in future studies of TSLP-dependent contact sensitization and skin immune responses.


Asunto(s)
Antígenos CD , Antígeno CD11b , Antígenos CD36 , Citocinas/inmunología , Células Dendríticas/inmunología , Dermatitis Alérgica por Contacto/inmunología , Dermis/inmunología , Cadenas alfa de Integrinas , Animales , Antígenos Dermatofagoides/inmunología , Antígenos Dermatofagoides/toxicidad , Células Dendríticas/patología , Dermatitis Alérgica por Contacto/patología , Dermis/patología , Escherichia coli/inmunología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Ratones , Mycobacterium bovis/inmunología , Receptores CCR7/inmunología , Factor de Transcripción STAT5/inmunología , Linfopoyetina del Estroma Tímico
4.
Cell Rep ; 43(7): 114364, 2024 Jul 23.
Artículo en Inglés | MEDLINE | ID: mdl-38900635

RESUMEN

Immunoregulatory mechanisms established in the lymphoid organs are vital for preventing autoimmunity. However, the presence of similar mechanisms in non-lymphoid tissues remains unclear. Through transcriptomic and lipidomic analyses, we find a negative association between psoriasis and fatty acid metabolism, as well as Th2 signature. Homeostatic expression of liver X receptor (LXR) and peroxisome proliferator-activated receptor gamma (PPARγ) is essential for maintaining fatty acid metabolism and for conferring resistance to psoriasis in mice. Perturbation of signal transducer and activator of transcription 6 (STAT6) diminishes the homeostatic levels of LXR and PPARγ. Furthermore, mice lacking STAT6, interleukin 4 receptor alpha (IL-4Rα), or IL-13, but not IL-4, exhibit increased susceptibility to psoriasis. Under steady state, innate lymphoid cells (ILCs) are the primary producers of IL-13. In human skin, inhibiting tonic type 2 immunity exacerbates psoriasis-like inflammation and IL-17A, while activating LXR or PPARγ inhibits them. Hence, we propose that tonic type 2 immunity, driven by IL-13-producing ILCs, represents a crucial tissue checkpoint that represses autoimmunity and maintains lipid homeostasis in the skin.


Asunto(s)
Autoinmunidad , Receptores X del Hígado , PPAR gamma , Piel , Animales , Piel/inmunología , Piel/metabolismo , Piel/patología , Humanos , Receptores X del Hígado/metabolismo , Ratones , PPAR gamma/metabolismo , Psoriasis/inmunología , Psoriasis/patología , Psoriasis/metabolismo , Ratones Endogámicos C57BL , Interleucina-13/metabolismo , Factor de Transcripción STAT6/metabolismo , Inmunidad Innata , Masculino , Femenino , Linfocitos/inmunología , Linfocitos/metabolismo
5.
Cell Rep ; 42(12): 113433, 2023 12 26.
Artículo en Inglés | MEDLINE | ID: mdl-38029739

RESUMEN

IL-31 receptor blockade suppresses pruritus of atopic dermatitis. However, cell-type-specific contributions of IL-31 receptor to itch, its expression mechanism, and the downstream signaling pathway to induce itch remain unknown. Here, using conditional knockout mice, we demonstrate that IL-31-induced itch requires sensory neuronal IL-31 receptor and STAT3. We find that IL-31 receptor expression is dependent on STAT3 in sensory neurons. In addition, pharmacological experiments suggest that STAT3 activation is important for the itch-inducing signaling downstream of the IL-31 receptor. A cutaneous IL-31 injection induces the nuclear accumulation of activated STAT3 first in sensory neurons that abundantly express IL-31 receptor and then in other itch-transmitting neurons. IL-31 enhances itch induced by various pruritogens including even chloroquine. Finally, pruritus associated with dermatitis is partially dependent on sensory neuronal IL-31 receptor and strongly on sensory neuronal STAT3. Thus, sensory neuronal STAT3 is essential for IL-31-induced itch and further contributes to IL-31-independent inflammatory itch.


Asunto(s)
Dermatitis Atópica , Prurito , Animales , Ratones , Dermatitis Atópica/metabolismo , Expresión Génica , Ratones Noqueados , Prurito/inducido químicamente , Prurito/genética , Prurito/metabolismo , Células Receptoras Sensoriales/metabolismo , Piel/metabolismo
6.
Sci Rep ; 9(1): 8625, 2019 06 13.
Artículo en Inglés | MEDLINE | ID: mdl-31197234

RESUMEN

The epidermal barrier is thought to protect sensory nerves from overexposure to environmental stimuli, and barrier impairment leads to pathological conditions associated with itch, such as atopic dermatitis (AD). However, it is not known how the epidermal barrier continuously protects nerves for the sensory homeostasis during turnover of the epidermis. Here we show that epidermal nerves are contained underneath keratinocyte tight junctions (TJs) in normal human and mouse skin, but not in human AD samples or mouse models of chronic itch caused by epidermal barrier impairment. By intravital imaging of the mouse skin, we found that epidermal nerve endings were frequently extended and retracted, and occasionally underwent local pruning. Importantly, the epidermal nerve pruning took place rapidly at intersections with newly forming TJs in the normal skin, whereas this process was disturbed during chronic itch development. Furthermore, aberrant Ca2+ increases in epidermal nerves were induced in association with the disturbed pruning. Finally, TRPA1 inhibition suppressed aberrant Ca2+ increases in epidermal nerves and itch. These results suggest that epidermal nerve endings are pruned through interactions with keratinocytes to stay below the TJ barrier, and that disruption of this mechanism may lead to aberrant activation of epidermal nerves and pathological itch.


Asunto(s)
Epidermis/inervación , Epidermis/patología , Homeostasis , Tejido Nervioso/patología , Prurito/patología , Animales , Calcio/metabolismo , Enfermedad Crónica , Dermatitis Atópica/patología , Humanos , Queratinocitos/patología , Ratones Endogámicos C57BL , Terminaciones Nerviosas/patología , Células Receptoras Sensoriales/patología , Canal Catiónico TRPA1/metabolismo , Uniones Estrechas/patología
7.
J Exp Med ; 214(1): 125-142, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27913566

RESUMEN

The dendritic cell signals required for the in vivo priming of IL-4-producing T cells are unknown. We used RNA sequencing to characterize DCs from skin LN of mice exposed to two different Th2 stimuli: the helminth parasite Nippostrongylus brasiliensis (Nb) and the contact sensitizer dibutyl phthalate (DBP)-FITC. Both Nb and DBP-FITC induced extensive transcriptional changes that involved multiple DC subsets. Surprisingly, these transcriptional changes were highly distinct in the two models, with only a small number of genes being similarly regulated in both conditions. Pathway analysis of expressed genes identified no shared pathways between Nb and DBP-FITC, but revealed a type-I IFN (IFN-I) signature unique to DCs from Nb-primed mice. Blocking the IFN-I receptor at the time of Nb treatment had little effect on DC migration and antigen transport to the LN, but inhibited the up-regulation of IFN-I-induced markers on DCs and effectively blunted Th2 development. In contrast, the response to DBP-FITC was not affected by IFN-I receptor blockade, a finding consistent with the known dependence of this response on the innate cytokine TSLP. Thus, the priming of Th2 responses is associated with distinct transcriptional signatures in DCs in vivo, reflecting the diverse environments in which Th2 immune responses are initiated.


Asunto(s)
Células Dendríticas/inmunología , Piel/inmunología , Células Th2/inmunología , Animales , Inmunoglobulinas/fisiología , Interferón Tipo I/fisiología , Ratones , Ratones Endogámicos C57BL , Nippostrongylus/inmunología , Receptor de Interferón alfa y beta/fisiología , Receptores de Citocinas/fisiología , Transcripción Genética
8.
J Immunol Methods ; 406: 104-9, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24556588

RESUMEN

Splenic langerin(+) CD8α(+) dendritic cells (DCs) have exhibited a critical role in cross-priming CD8(+) T cell responses. To further study the roles of this DC subset, a protocol for the continuous depletion of langerin(+) CD8α(+) DCs was established using the pre-existing lang-DTREGFP mouse model. Due to the fast turnover rate of splenic CD8α(+) DCs, maintaining the depletion of langerin(+) CD8α(+) DCs required multiple diphtheria toxin (DT) treatments. We found that prolonged treatment with DT did not cause weight loss, or neutrophilia, as reported in some DT-based depletion models. Therefore, the in vivo depletion of murine langerin(+) CD8α(+) DCs can be maintained over time to analyse their function during the full course of an immune response.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Toxina Diftérica/inmunología , Depleción Linfocítica , Animales , Presentación de Antígeno/inmunología , Antígenos de Superficie/inmunología , Antígenos CD8/inmunología , Toxina Diftérica/administración & dosificación , Lectinas Tipo C/inmunología , Activación de Linfocitos/inmunología , Lectinas de Unión a Manosa/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Bazo/citología , Bazo/inmunología
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