Distinct, Specific IL-17- and IL-22-Producing CD4+ T Cell Subsets Contribute to the Human Anti-Mycobacterial Immune Response

Scriba, Thomas J.; Kalsdorf, Barbara; Abrahams, Deborah-Ann; Isaacs, Fatima; Hofmeister, Jessica; Black, Gillian F.; Hassan, Hisham Y.; Wilkinson, Robert J.; Walzl, Gerhard; Gelderbloem, Sebastian; Mahomed, Hassan; Hussey, Gregory; Hanekom, Willem A.

doi:10.4049/jimmunol.180.3.1962

Cited by 377 publications

(398 citation statements)

References 71 publications

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“…Finally, CD161 selectively expressed in Th17 cells [9,36] was absent in IL-22 1 IL-17A À IFN-g À singlepositive T cells. Furthermore, our data regarding the dissociated IL-22 and IL-17 production are consistent with recent reports showing that skin-homing memory T cells [31,32], T cells present in the skin of individuals affected by atopic dermatitis [41], plaque psoriasis, allergic contact dermatitis [33] and T cells responding to mycobacteria [42] or Candida albicans [43] produce IL-22 but not IL-17A or IFN-g. Of interest, human Langerhans cells appear to favor the induction of CD4 1 T cells producing IL-22 but not IL-17, thus stressing a preferential role of these cells in skin immunosurveillance [44]. Finally, Notch signaling has been shown to selectively drive IL-22 but not IL-17A production in murine CD4 1 T cells by inducing endogenous AHR ligands [45].…”

Section: Discussionsupporting

confidence: 92%

Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL‐22 and IL‐17 production by human T helper cells

Ramirez¹,

Brembilla²,

Sorg³

et al. 2010

Eur J Immunol

165

141

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Ligands of the aryl hydrocarbon receptor (AHR), a transcription factor mediating the effects of dioxin, favor Th17 differentiation and exacerbate autoimmunity in mice. We investigated how AHR ligands affected human T-cell polarization. We found that the high affinity and stable AHR-ligand dioxin as well as the natural AHR-ligand 6-formylinolo [3,2-b] carbazole induced the downstream AHR-target cytochrome P450A1, and without affecting IFN-c, they enhanced IL-22 while simultaneously decreasing IL-17A production by CD4 1 T cells. The specific AHRinhibitor CH-223191 abolished these effects. Furthermore, blockade of IL-23 and IL-1, important for Th17 expansion, profoundly decreased IL-17A but not IL-22 production. AHR agonists reduced the expression of the Th17 master transcription factor retinoic acid-related orphan receptor C (RORC), without affecting T-bet, GATA-3 and Foxp3. They also decreased the expression of the IL-23 receptor. Importantly, AHR-ligation did not only decrease the number of Th17 cells but also primed naïve CD4 1 T cells to produce IL-22 without IL-17 and IFN-c. Furthermore, IL-22 single producers did not express CD161, which distinguished them from the CD161 1 Th17 cells. Hence, our data provide compelling evidence that AHR activation participates in shaping human CD4 1 T-cell polarization favoring the emergence of a distinct subset of IL-22-producing cells that are independent from the Th17 lineage. IntroductionLocal cytokine milieu during antigen presentation profoundly affects the differentiation program of CD4 1 T cells [1]. In the mouse, TGF-b, in the presence of IL-6 and pro-inflammatory cytokines, favors the emergence of Th17 cells that produce IL-17 and express the master transcription factor retinoic acid-related orphan receptor (ROR)gt [2][3][4][5][6]. Th17 cells are expanded and terminally differentiated in the presence of . Human Th17 cells may be generated in the presence of IL-1 and IL-23; IL-1 and IL-6; or . Th17 cells express CCR6 and 2450produce the CCR6-ligand CCL20, thereby amplifying Th17 cell recruitment at sites of inflammation [11]. IL-22, a member of the IL-10-family, is produced by Th17 cells, and to some extent by Th1 cells, NKT cells, NK cells and lymphoid tissue inducer-like cells [12]. IL-22 signals via a receptor consisting of IL-22R and IL-10R2 subunits [11]. Cells of hemapoietic origin do not express IL-22R; instead, IL-2R is highly expressed by epithelial cells of the gastrointestinal tract and the skin. In the mouse, IL-23 was shown to drive preferential expansion of cells that co-express IL-22 and IL-17, that may synergize to augment the expression of genes involved in defense against microbial pathogens [13,14]. However, several mouse models of infection and autoimmunity suggested distinct roles for .In addition to cytokines, other mediators may impact CD4 1 T-cell differentiation. We and others have shown that prostaglandin E2 (PGE2) favors human Th17 expansion [20][21][22]. Furthermore, ligands of the aryl hydrocarbon receptor (AHR) exert a role. AHR is a...

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Section: Discussionsupporting

confidence: 92%

Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL‐22 and IL‐17 production by human T helper cells

Ramirez¹,

Brembilla²,

Sorg³

et al. 2010

Eur J Immunol

165

141

View full text Add to dashboard Cite

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“…However, the lack of expression of IL-22 and IL-23R on these IL-17-producing Th cells makes it premature to define them as Th17 cells without further characterisation. With this in mind, it is interesting to note that there is previous evidence, fully in line with the current data, on the presence of Th cells that produce IL-17 but not IL-22 in studies on blood cells during mycobacterial infection [28] and on skin in psoriasis and atopic dermatitis [29]. The soluble IL-22 that was found in the cell-free BAL samples may originate from cells other than T-cells, such as lung macrophages, which have been implicated as possible IL-22-producers in a previous study on humans [30].…”

Section: Increase In Effector Molecules Downstream Of Il-17 and Il-22supporting

confidence: 64%

Interleukin-17-producing T-helper cells and related cytokines in human airways exposed to endotoxin

Glader¹,

Smith²,

Malmhäll³

et al. 2010

Eur Respir J

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Previous studies on mouse models have indicated that interleukin (IL)-17 and IL-17-producing T-helper (Th) cells are important for pulmonary host defence against Gram-negative bacteria. Human correlates to these findings have not yet been demonstrated. The aim of the present study was to determine whether or not IL-17-producing Th cells are present and whether IL-17 and other Th17-associated cytokines are involved in the immunological response to endotoxin in human airways.Segmental exposure to endotoxin and contralateral exposure to vehicle were performed in the lungs of healthy volunteers, with subsequent bronchoalveolar lavage 12 or 24 h after exposure to study local changes in cytokines and inflammatory cells.Endotoxin exposure increased concentrations of IL-17, IL-22 and their downstream effector molecules, human b-defensin-2 and IL-8/CXC chemokine ligand 8, in bronchoalveolar lavage fluid. Th cells with the capacity to produce IL-17 were found among the bronchoalveolar lavage cells, and expression of IL-17 mRNA correlated with expression of the transcription factor, retinoic-acidreceptor-related orphan receptor C variant 2. Moreover, endotoxin increased the numbers of neutrophils, macrophages and IL-17-producing T-cells, as well as the concentration of the Th17-regulating cytokines, IL-21 and IL-23.In conclusion, IL-17-producing Th cells are present, and IL-17, as well as other Th17-associated cytokines, is involved in the immunological response to endotoxin in human airways.

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“…Furthermore, an increase of IL-17A-producing TCR gd T cells was reported in peripheral blood of patients with tuberculosis (51). In contrast, a decrease of mycobacterial Ag-specific IL-17A-producing CD4 + T cells was reported in patients with tuberculosis (49,52). The observations suggest that contact with mycobacteria induces human IL-17A-producing TCR ab or TCR gd T cells, but the mycobacterial Agspecific Th17-type T cells decrease in active tuberculosis.…”

Section: Discussionmentioning

confidence: 53%

Essential Role of IL-17A in the Formation of a Mycobacterial Infection-Induced Granuloma in the Lung

Yoshida

Umemura

Yahagi

et al. 2010

The Journal of Immunology

355

261

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Granulomas play an essential role in the sequestration and killing of mycobacteria in the lung; however, the mechanisms of their development and maturation are still not clearly understood. IL-17A is involved in mature granuloma formation in the mycobacteria-infected lung. Therefore, IL-17A gene-knockout (KO) mice fail to develop mature granulomas in the Mycobacterium bovis bacille Calmette-Guérin (BCG)-infected lung. This study analyzed the mechanism of IL-17A–dependent mature granuloma formation in the mycobacteria-infected lung. The IL-17A KO mice showed a normal level of nascent granuloma formation on day 14 but failed to develop mature granulomas on day 28 after the BCG infection in the lung. The observation implies that IL-17A is required for the maturation of granuloma from the nascent to mature stage. TCR γδ T cells expressing TCR Vγ4 or Vγ6 were identified as the major IL-17A–producing cells that resided in the BCG-induced lung granuloma. The adoptive transfer of the IL-17A–producing TCR γδ T cells reconstituted granuloma formation in the IL-17A KO mice. The expression of ICAM-1 and LFA-1, which are adhesion molecules important in granuloma formation, decreased in the lung of the BCG-infected IL-17A KO mice, and their expression was induced on BCG-infected macrophages in coculture with IL-17A–producing TCR γδ T cells. Furthermore, IL-17A KO mice showed not only an impaired mature granuloma formation, but also an impaired protective response to virulent Mycobacterium tuberculosis. Therefore, IL-17A produced by TCR γδ T cells plays a critical role in the prevention of M. tuberculosis infection through the induction of mature granuloma formation.

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Distinct, Specific IL-17- and IL-22-Producing CD4+ T Cell Subsets Contribute to the Human Anti-Mycobacterial Immune Response

Cited by 377 publications

References 71 publications

Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL‐22 and IL‐17 production by human T helper cells

Activation of the aryl hydrocarbon receptor reveals distinct requirements for IL‐22 and IL‐17 production by human T helper cells

Interleukin-17-producing T-helper cells and related cytokines in human airways exposed to endotoxin

Essential Role of IL-17A in the Formation of a Mycobacterial Infection-Induced Granuloma in the Lung

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