IL-17+ mast cell/T helper cell axis in the early stages of acne

Acne is a multifactorial disease driven by physiological changes occurring during puberty in the pilosebaceous unit (PSU) that leads to sebum overproduction and a dysbiosis involving notably Cutibacterium acnes. These changes in the PSU microenvironment lead to a shift from a homeostatic to an inflammatory state. Indeed, immunohistochemical analyses have revealed that inflammation and lymphocyte infiltration can be detected even in the infraclinical acneic stages, highlighting the importance of the early stages of the disease. In this study, we utilized a robust multi-pronged approach that included flow cytometry, confocal microscopy, and bioinformatics to comprehensively characterize the evolution of the infiltrating and resident immune cell populations in acneic lesions, beginning in the early stages of their development. Using a discovery cohort of 15 patients, we demonstrated that the composition of immune cell infiltrate is highly dynamic in nature, with the relative abundance of different cell types changing significantly as a function of clinical lesion stage. Within the stages examined, we identified a large population of CD69+ CD4+ T cells, several populations of activated antigen presenting cells, and activated mast cells producing IL-17. IL-17+ mast cells were preferentially located in CD4+ T cell rich areas and we showed that activated CD4+ T cells license mast cells to produce IL-17. Our study reveals that mast cells are the main IL-17 producers in the early stage of acne, underlying the importance of targeting the IL-17+ mast cell/T helper cell axis in therapeutic approaches.

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Generation of IL-8 and IL-9 Producing CD4+T Cells Is Affected by Th17 Polarizing Conditions and AHR Ligands

Mediators of Inflammation ◽

10.1155/2014/182549 ◽

2014 ◽

Vol 2014 ◽

pp. 1-14 ◽

Cited By ~ 13

Author(s):

Michaela Gasch ◽

Tina Goroll ◽

Mario Bauer ◽

Denise Hinz ◽

Nicole Schütze ◽

...

Keyword(s):

T Cells ◽

T Helper Cells ◽

Th17 Cells ◽

Immune Cell ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Helper Cells ◽

Aryl Hydrocarbon

The T helper cell subsets Th1, Th2, Th17, and Treg play an important role in immune cell homeostasis, in host defense, and in immunological disorders. Recently, much attention has been paid to Th17 cells which seem to play an important role in the early phase of the adoptive immune response and autoimmune disease. When generating Th17 cells underin vitroconditions the amount of IL-17A producing cells hardly exceeds 20% while the nature of the remaining T cells is poorly characterized. As engagement of the aryl hydrocarbon receptor (AHR) has also been postulated to modulate the differentiation of T helper cells into Th17 cells with regard to the IL-17A expression we ask how far do Th17 polarizing conditions in combination with ligand induced AHR activation have an effect on the production of other T helper cell cytokines. We found that a high proportion of T helper cells cultured under Th17 polarizing conditions are IL-8 and IL-9 single producing cells and that AHR activation results in an upregulation of IL-8 and a downregulation of IL-9 production. Thus, we have identified IL-8 and IL-9 producing T helper cells which are subject to regulation by the engagement of the AHR.

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Defective T-helper cell function after T-cell–depleting therapy affecting naive and memory populations

Blood ◽

10.1182/blood.v99.11.4053 ◽

2002 ◽

Vol 99 (11) ◽

pp. 4053-4062 ◽

Cited By ~ 23

Author(s):

Andreas Heitger ◽

Patricia Winklehner ◽

Petra Obexer ◽

Johannes Eder ◽

Claudia Zelle-Rieser ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Mononuclear Cells ◽

Cell Function ◽

Interleukin 2 ◽

T Helper Cell ◽

Helper Cell ◽

High Dose ◽

T Helper

Impaired T-cell function after T-cell– depleting (TCD) therapy has been hypothesized to be related to a transient predominance of extrathymically expanding memory T cells. To test whether after TCD therapy the naive T-helper cell population is functionally intact, the in vitro immune response of CD4+CD45RA+ (naive) and of CD4+CD45RA− (memory) cells to polyclonal mitogens (immobilized anti-CD3, phytohemagglutinin) was analyzed by flow cytometry in 22 pediatric patients after high-dose chemotherapy (including 5 after autologous and 5 after allogeneic stem cell support). At 1 to 3 months after TCD therapy, patient samples showing decreased lymphoproliferative responses also showed a reduced induction of the early activation marker CD69 by CD4+ T cells from 4 to 72 hours after stimulation even when supplemented with exogenous interleukin-2. This defect affected CD4+CD45RA− cells, but, strikingly, also CD4+CD45RA+ cells, including samples in which CD4+CD45RA+ cells were more than 90/μL, thus indicating ongoing thymopoiesis. Histogram analyses showed the median peak channel of CD69 in control CD4+CD45RA+cells rising 98-fold (median) but only 28-fold in patient cells (P < .0001). Apoptosis as detected by annexin V staining was increased in resting patient CD4+ T cells (25% versus 6%) and also affected CD4+CD45RA+ cells (12% versus 5%, P < .01). When peripheral blood mononuclear cells (PBMCs) were enriched for T cells, stimulatory responses of CD4+ cells and of CD4+CD45RA+ cells markedly improved. Thus, after TCD therapy suppressor factors contained in the non–T-cell fraction of PBMCs may affect T-helper cells irrespective of their naive or memory phenotype thus extending T-cell dysfunction to the presumably thymus-dependently regenerated T cells.

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Aberrantly methylated DNA regions lead to low activation of CD4+ T-cells in IgA nephropathy

Clinical Science ◽

10.1042/cs20150711 ◽

2016 ◽

Vol 130 (9) ◽

pp. 733-746 ◽

Cited By ~ 10

Author(s):

Fabio Sallustio ◽

Grazia Serino ◽

Sharon N. Cox ◽

Alessandra Dalla Gassa ◽

Claudia Curci ◽

...

Keyword(s):

T Cells ◽

Iga Nephropathy ◽

Cd4 T Cells ◽

Signal Strength ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Methylated Dna

DNA regions abnormally methylated in IgAN patients led to the reduced TCR signal strength of CD4+ T-cells and to their anomalous response, explaining the T-helper cell imbalance.

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Comprehensive Intestinal T Helper Cell Profiling Reveals Specific Accumulation of IFN-γ+IL-17+Coproducing CD4+ T Cells in Active Inflammatory Bowel Disease

Inflammatory Bowel Diseases ◽

10.1097/mib.0000000000000210 ◽

2014 ◽

Vol 20 (12) ◽

pp. 2321-2329 ◽

Cited By ~ 71

Author(s):

Anna-Maria Globig ◽

Nadine Hennecke ◽

Bianca Martin ◽

Maximilian Seidl ◽

Günther Ruf ◽

...

Keyword(s):

Inflammatory Bowel Disease ◽

T Cells ◽

Bowel Disease ◽

Cd4 T Cells ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Specific Accumulation ◽

Inflammatory Bowel ◽

Ifn Γ

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IL-12– and IL-23–induced T helper cell subsets

Journal of Experimental Medicine ◽

10.1084/jem.20042279 ◽

2005 ◽

Vol 201 (2) ◽

pp. 169-171 ◽

Cited By ~ 105

Author(s):

Estelle Bettelli ◽

Vijay K. Kuchroo

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Th Cells ◽

Th 1

Traditionally, CD4+ T cells have been separated into two different subsets named T helper (Th)1 and Th2. A new IL-23–driven subset of Th cells called ThIL-17 has now been described. The data suggest that IL-23 plays an important role in the differentiation of autoreactive pathogenic T cells. Whether these IL-23–induced ThIL-17 cells are a unique subset or are related to other Th subsets is discussed.

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Age-Related Dynamics of Circulating Innate Lymphoid Cells in an African Population

Frontiers in Immunology ◽

10.3389/fimmu.2020.594107 ◽

2020 ◽

Vol 11 ◽

Author(s):

Alansana Darboe ◽

Carolyn M. Nielsen ◽

Asia-Sophia Wolf ◽

Jacob Wildfire ◽

Ebrima Danso ◽

...

Keyword(s):

T Cells ◽

Life Course ◽

Peripheral Blood ◽

Cd4 T Cells ◽

T Helper Cell ◽

Helper Cell ◽

Effector Memory ◽

T Helper ◽

Age Related ◽

The Life Course

Innate lymphoid cell (ILC) lineages mirror those of CD4+ T helper cell subsets, producing type 1, 2 and 3 cytokines respectively. Studies in adult human populations have shown contributions of non-cytotoxic ILC to immune regulation or pathogenesis in a wide range of diseases and have prompted investigations of potential functional redundancy between ILC and T helper cell compartments in neonates and children. To investigate the potential for ILC to contribute to immune responses across the human lifespan, we examined the numbers and frequencies of peripheral blood ILC subsets in a cohort of Gambians aged between 5 and 73 years of age. ILC2 were the most abundant peripheral blood ILC subset in this Gambian cohort, while ILC1 were the rarest at all ages. Moreover, the frequency of ILC1s (as a proportion of all lymphocytes) was remarkably stable over the life course whereas ILC3 cell frequencies and absolute numbers declined steadily across the life course and ILC2 frequencies and absolute numbers declined from childhood until the age of approx. 30 years of age. Age-related reductions in ILC2 cell numbers appeared to be partially offset by increasing numbers of total and GATA3+ central memory (CD45RA-CCR7+) CD4+ T cells, although there was also a gradual decline in numbers of total and GATA3+ effector memory (CD45RA-CCR7-) CD4+ T cells. Despite reduced overall abundance of ILC2 cells, we observed a coincident increase in the proportion of CD117+ ILC2, indicating potential for age-related adaptation of these cells in childhood and early adulthood. While both CD117+ and CD117- ILC2 cells produced IL-13, these responses occurred predominantly within CD117- cells. Furthermore, comparison of ILC frequencies between aged-matched Gambian and UK young adults (25–29 years) revealed an overall higher proportion of ILC1 and ILC2, but not ILC3 in Gambians. Thus, these data indicate ongoing age-related changes in ILC2 cells throughout life, which retain the capacity to differentiate into potent type 2 cytokine producing cells, consistent with an ongoing role in immune modulation.

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Combined Stimulation with the T Helper Cell Type 2 Cytokines Interleukin (Il)-4 and IL-10 Induces Mouse Mast Cell Apoptosis

Journal of Experimental Medicine ◽

10.1084/jem.192.8.1093 ◽

2000 ◽

Vol 192 (8) ◽

pp. 1093-1104 ◽

Cited By ~ 65

Author(s):

C. Fitzhugh Yeatman ◽

Sarah M. Jacobs-Helber ◽

Paria Mirmonsef ◽

Sheila R. Gillespie ◽

Lawrence Andrew Bouton ◽

...

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Allergic Disease ◽

T Helper Cell ◽

Helper Cell ◽

Th2 Cytokines ◽

Cell Type ◽

T Helper ◽

Helper Cell Type

Mast cells are found in connective and mucosal tissues throughout the body. Their activation via immunoglobulin E (IgE)–antigen interactions is promoted by T helper cell type 2 (Th2) cytokines and leads to the sequelae of allergic disease. We now report a mechanism by which Th2 cytokines can regulate mast cell survival. Specifically, we find that interleukin (IL)-4 and IL-10 induce apoptosis in IL-3–dependent bone marrow–derived mast cells and peritoneal mast cells. This process required 6 d of costimulation with IL-3, IL-4, and IL-10, and expression of signal transducer and activator of transcription 6 (Stat6). Apoptosis was coupled with decreased expression of bcl-xL and bcl-2. While this process occurred independent of the Fas pathway, culture in IL-3+IL-4+IL-10 greatly sensitized mast cells to Fas-mediated death. Additionally, we found that IgE cross-linkage or stimulation with stem cell factor enhanced the apoptotic abilities of IL-4 and IL-10. Finally, IL-3–independent mastocytomas and mast cell lines were resistant to apoptosis induced by IL-3+IL-4+IL-10. These data offer evidence of Th2 cytokine–mediated homeostasis whereby these cytokines both elicit and limit allergic responses. Dysregulation of this pathway may play a role in allergic disease and mast cell tumor survival.

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