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Cell Host Microbe. 2008 Oct 16;4(4):337-49.
Specific microbiota direct the
differentiation of IL-17-producing T-helper
cells in the mucosa of the small intestine.
Ivanov II, Frutos Rde L, Manel N, Yoshinaga K, Rifkin DB, Sartor RB, Finlay BB, Littman
DR.
Source
Kimmel Center for Biology and Medicine of the Skirball Institute, Department of
Microbiology, New York University School of Medicine, New York, NY 10016, USA.
Abstract
The requirements for in vivo steady state differentiation of IL-17-producing T-helper (Th17)
cells, which are potent inflammation effectors, remain obscure. We report that Th17 cell
differentiation in the lamina propria (LP) of the small intestine requires specific commensal
microbiota and is inhibited by treating mice with selective antibiotics. Mice from different
sources had marked differences in their Th17 cell numbers and animals lacking Th17 cells
acquired them after introduction of bacteria from Th17 cell-sufficient mice. Differentiation of
Th17 cells correlated with the presence of cytophaga-flavobacter-bacteroidetes (CFB)
bacteria in the intestine and was independent of toll-like receptor, IL-21 or IL-23 signaling,
but required appropriate TGF-beta activation. Absence of Th17 cell-inducing bacteria was
accompanied by increase in Foxp3+ regulatory T cells (Treg) in the LP. Our results suggest
that composition of intestinal microbiota regulates the Th17:Treg balance in the LP and may
thus influence intestinal immunity, tolerance, and susceptibility to inflammatory bowel
diseases.
Supplemental Content
Intestinal bacterial colonization induces
mutualistic regulatory T cell responses.
Geuking MB, Cahenzli J, Lawson MA, Ng DC, Slack E, Hapfelmeier S, McCoy KD,
Macpherson AJ.
Source
Maurice Müller Laboratories (DKF), Universitätsklinik für Viszerale Chirurgie und Medizin
Inselspital, Murtenstrasse 35, University of Bern, Bern, Switzerland. [email protected]
Abstract
Mammals harbor a dense commensal microbiota in the colon. Regulatory T (Treg) cells are
known to limit microbe-triggered intestinal inflammation and the CD4+ T cell compartment is
shaped by the presence of particular microbes or bacterial compounds. It is, however, difficult
to distinguish whether these effects reflect true mutualistic immune adaptation to intestinal
colonization or rather idiosyncratic immune responses. To investigate truly mutualistic CD4+
T cell adaptation, we used the altered Schaedler flora (ASF). Intestinal colonization resulted
in activation and de novo generation of colonic Treg cells. Failure to activate Treg cells
resulted in the induction of T helper 17 (Th17) and Th1 cell responses, which was reversed by
wild-type Treg cells. Efficient Treg cell induction was also required to maintain intestinal
homeostasis upon dextran sulfate sodium-mediated damage in the colon. Thus, microbiota
colonization-induced Treg cell responses are a fundamental intrinsic mechanism to induce and
maintain host-intestinal microbial T cell mutualism.
Copyright © 2011 Elsevier Inc. All rights reserved.
Supplemental Content
Semin Immunol. 2011 Apr;23(2):146-53. Epub 2011 Feb 3.
Microbiotal influence on T cell subset
development.
Atarashi K, Umesaki Y, Honda K.
Source
Department of Immunology, Graduate School of Medicine, The University of Tokyo, Tokyo,
Japan.
Abstract
The mammalian alimentary tract harbors hundreds of bacterial species that constitute the
indigenous microbial flora. The indigenous microbial flora has long been appreciated for its
role in host immune system development. Recent reports suggest that components of the
microbial flora differentially affect the proportion and number of functionally distinct subsets
of T cells in the intestine. Substantial changes in the composition of the microbiota are
associated with inflammatory bowel disease. This review will discuss the importance of
individual species of microbial flora in the induction of T cell subsets, particularly Th17 cells
and regulatory T (Treg) cells in the intestine.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Supplemental Content
J Immunol. 2010 Jun 15;184(12):6799-806. Epub 2010 May 19.
Downregulation of Th17 cells in the small
intestine by disruption of gut flora in the
absence of retinoic acid.
Cha HR, Chang SY, Chang JH, Kim JO, Yang JY, Kim CH, Kweon MN.
Source
Mucosal Immunology Section, Laboratory Science Division, International Vaccine Institute,
Seoul, Korea.
Abstract
Retinoic acid (RA), a well-known vitamin A metabolite, mediates inhibition of the IL-6driven induction of proinflammatory Th17 cells and promotes anti-inflammatory regulatory T
cell generation in the presence of TGF-beta, which is mainly regulated by dendritic cells. To
directly address the role of RA in Th17/regulatory T cell generation in vivo, we generated
vitamin A-deficient (VAD) mice by continuous feeding of a VAD diet beginning in gestation.
We found that a VAD diet resulted in significant inhibition of Th17 cell differentiation in the
small intestine lamina propria by as early as age 5 wk. Furthermore, this diet resulted in low
mRNA expression levels of IL-17, IFN regulatory factor 4, IL-21, IL-22, and IL-23 without
alteration of other genes, such as RORgammat, TGF-beta, IL-6, IL-25, and IL-27 in the small
intestine ileum. In vitro results of enhanced Th17 induction by VAD dendritic cells did not
mirror in vivo results, suggesting the existence of other regulation factors. Interestingly, the
VAD diet elicited high levels of mucin MUC2 by goblet cell hyperplasia and subsequently
reduced gut microbiome, including segmented filamentous bacteria. Much like wild-type
mice, the VAD diet-fed MyD88-/-TRIF-/- mice had significantly fewer IL-17-secreting CD4+
T cells than the control diet-fed MyD88-/-TRIF-/- mice. The results strongly suggest that RA
deficiency altered gut microbiome, which in turn inhibited Th17 differentiation in the small
intestine lamina propria.
Supplemental Content
J Exp Med. 2009 Feb 16;206(2):299-311. Epub 2009 Feb 9.
Th17 cells and IL-17 receptor signaling are
essential for mucosal host defense against
oral candidiasis.
Conti HR, Shen F, Nayyar N, Stocum E, Sun JN, Lindemann MJ, Ho AW, Hai JH, Yu JJ,
Jung JW, Filler SG, Masso-Welch P, Edgerton M, Gaffen SL.
Source
Department of Oral Biology, School of Dental Medicine, State University of New York,
Buffalo, NY 14201, USA.
Abstract
The commensal fungus Candida albicans causes oropharyngeal candidiasis (OPC; thrush) in
settings of immunodeficiency. Although disseminated, vaginal, and oral candidiasis are all
caused by C. albicans species, host defense against C. albicans varies by anatomical location.
T helper 1 (Th1) cells have long been implicated in defense against candidiasis, whereas the
role of Th17 cells remains controversial. IL-17 mediates inflammatory pathology in a gastric
model of mucosal candidiasis, but is host protective in disseminated disease. Here, we directly
compared Th1 and Th17 function in a model of OPC. Th17-deficient (IL-23p19(-/-)) and IL17R-deficient (IL-17RA(-/-)) mice experienced severe OPC, whereas Th1-deficient (IL12p35(-/-)) mice showed low fungal burdens and no overt disease. Neutrophil recruitment was
impaired in IL-23p19(-/-) and IL-17RA(-/-), but not IL-12(-/-), mice, and TCR-alphabeta cells
were more important than TCR-gammadelta cells. Surprisingly, mice deficient in the Th17
cytokine IL-22 were only mildly susceptible to OPC, indicating that IL-17 rather than IL-22 is
vital in defense against oral candidiasis. Gene profiling of oral mucosal tissue showed strong
induction of Th17 signature genes, including CXC chemokines and beta defensin-3. Saliva
from Th17-deficient, but not Th1-deficient, mice exhibited reduced candidacidal activity.
Thus, the Th17 lineage, acting largely through IL-17, confers the dominant response to oral
candidiasis through neutrophils and antimicrobial factors.
Supplemental Content
J Clin Invest. 2010 May 3;120(5):1762-73. doi: 10.1172/JCI40891. Epub 2010 Apr 1.
IL-17 is essential for host defense against
cutaneous Staphylococcus aureus infection
in mice.
Cho JS, Pietras EM, Garcia NC, Ramos RI, Farzam DM, Monroe HR, Magorien JE, Blauvelt
A, Kolls JK, Cheung AL, Cheng G, Modlin RL, Miller LS.
Source
Division of Dermatology, UCLA, Los Angeles, California 90095, USA.
Abstract
Staphylococcus aureus is the most common cause of skin and soft tissue infections, and
rapidly emerging antibiotic-resistant strains are creating a serious public health concern. If
immune-based therapies are to be an alternative to antibiotics, greater understanding is
needed of the protective immune response against S. aureus infection in the skin. Although
neutrophil recruitment is required for immunity against S. aureus, a role for T cells has been
suggested. Here, we used a mouse model of S. aureus cutaneous infection to investigate the
contribution of T cells to host defense. We found that mice deficient in gammadelta but not
alphabeta T cells had substantially larger skin lesions with higher bacterial counts and
impaired neutrophil recruitment compared with WT mice. This neutrophil recruitment was
dependent upon epidermal Vgamma5+ gammadelta T cell production of IL-17, but not IL-21
and IL-22. Furthermore, IL-17 induction required IL-1, TLR2, and IL-23 and was critical for
host defense, since IL-17R-deficient mice had a phenotype similar to that of gammadelta T
cell-deficient mice. Importantly, gammadelta T cell-deficient mice inoculated with S. aureus
and treated with a single dose of recombinant IL-17 had lesion sizes and bacterial counts
resembling those of WT mice, demonstrating that IL-17 could restore the impaired immunity
in these mice. Our study defines what we believe to be a novel role for IL-17-producing
epidermal gammadelta T cells in innate immunity against S. aureus cutaneous infection.
Supplemental Content
J Exp Med. 2009 Feb 16;206(2):299-311. Epub 2009 Feb 9.
Th17 cells and IL-17 receptor signaling are
essential for mucosal host defense against
oral candidiasis.
Conti HR, Shen F, Nayyar N, Stocum E, Sun JN, Lindemann MJ, Ho AW, Hai JH, Yu JJ,
Jung JW, Filler SG, Masso-Welch P, Edgerton M, Gaffen SL.
Source
Department of Oral Biology, School of Dental Medicine, State University of New York,
Buffalo, NY 14201, USA.
Abstract
The commensal fungus Candida albicans causes oropharyngeal candidiasis (OPC; thrush) in
settings of immunodeficiency. Although disseminated, vaginal, and oral candidiasis are all
caused by C. albicans species, host defense against C. albicans varies by anatomical location.
T helper 1 (Th1) cells have long been implicated in defense against candidiasis, whereas the
role of Th17 cells remains controversial. IL-17 mediates inflammatory pathology in a gastric
model of mucosal candidiasis, but is host protective in disseminated disease. Here, we directly
compared Th1 and Th17 function in a model of OPC. Th17-deficient (IL-23p19(-/-)) and IL17R-deficient (IL-17RA(-/-)) mice experienced severe OPC, whereas Th1-deficient (IL12p35(-/-)) mice showed low fungal burdens and no overt disease. Neutrophil recruitment was
impaired in IL-23p19(-/-) and IL-17RA(-/-), but not IL-12(-/-), mice, and TCR-alphabeta cells
were more important than TCR-gammadelta cells. Surprisingly, mice deficient in the Th17
cytokine IL-22 were only mildly susceptible to OPC, indicating that IL-17 rather than IL-22 is
vital in defense against oral candidiasis. Gene profiling of oral mucosal tissue showed strong
induction of Th17 signature genes, including CXC chemokines and beta defensin-3. Saliva
from Th17-deficient, but not Th1-deficient, mice exhibited reduced candidacidal activity.
Thus, the Th17 lineage, acting largely through IL-17, confers the dominant response to oral
candidiasis through neutrophils and antimicrobial factors.
Comment in

J Exp Med. 2009 Feb 16;206(2):269-73.
Supplemental Content
Evid Based Complement Alternat Med. 2009 Jul 21. [Epub ahead of print]
The Role of Th17 in Neuroimmune
Disorders: A Target for CAM Therapy. Part
III.
Vojdani A, Lambert J, Kellermann G.
Source
Immunosciences Lab., Inc., 822 S. Robertson Boulevard, Suite 312 Los Angeles, CA 90035,
USA. [email protected].
Abstract
Abundant research has mapped the inflammatory pathways leading to autoimmunity and
neuroinflammatory disorders. The latest T helper to be identified, Th17, through its
proinflammatory cytokine IL-17, plays a pathogenic role in many inflammatory conditions.
Today, healthcare providers have a wealth of anti-inflammatory agents from which to choose.
On one hand, pharmaceutical companies market brand-name drugs direct to the public and
physicians. Medical botanical knowledge, on the other hand, has been passed down from
generation to generation. The demands for natural healing therapies have brought
corresponding clinical and laboratory research studies to elucidate the medicinal properties of
alternative practices. With a variety of options, it can be difficult to pinpoint the proper antiinflammatory agent for each case presented. In this review, the authors highlight a vast array
of anti-inflammatory medicaments ranging from drugs to vitamins and from botanicals to
innate molecules. This compilation may serve as a guide for complimentary and alternative
healthcare providers who need to target neuroinflammation driven by Th17 and its
inflammatory cytokine IL-17. By understanding the mechanisms of anti-inflammatory agents,
CAM practitioners can tailor therapeutic interventions to fit the needs of the patient, thereby
providing faster relief from inflammatory complaints.
Supplemental Content
Evid Based Complement Alternat Med. 2009 Jul 21. [Epub ahead of print]
The Role of Th17 in Neuroimmune
Disorders: Target for CAM Therapy. Part
II.
Vojdani A, Lambert J.
Source
Immunosciences Lab., Inc., 822 S. Robertson Boulevard, Suite 312, Los Angeles, CA 90035,
USA. [email protected].
Abstract
Decades of research went into understanding the role that Th1 autoreactive T-cells play in
neuroinflammation. Here we describe another effector population, the IL-17-producing Thelper lineage (Th17), which drives the inflammatory process. Through the recruitment of
inflammatory infiltration neutrophils and the activation of matrix metalloproteinases, IL-17, a
cytokine secreted by Th17 cells, contributes to blood-brain barrier breakdown and the
subsequent attraction of macrophages and monocytes into the nervous system. The entry of
cells along with the local production of inflammatory cytokines leads to myelin and axonal
damage. This activation of the inflammatory response system is induced by different
pathogenic factors, such as gut bacterial endotoxins resulting in progressive
neurodegeneration by Th17 cells. Through the understanding of the role of bacterial
endotoxins and other pathogenic factors in the induction of autoimmune diseases by Th17
cells, CAM practitioners will be able to design CAM therapies targeting IL-17 activity.
Targeted therapy can restore the integrity of the intestinal and blood-brain barriers using
probiotics, N-acetyl-cysteine, alpha-lipoic acid, resveratrol and others for their patients with
autoimmunities, in particular those with neuroinflammation and neurodegeneration.
Supplemental Content
Evid Based Complement Alternat Med. 2009 Jul 21. [Epub ahead of print]
The Role of Th17 in Neuroimmune
Disorders: Target for CAM Therapy. Part I.
Vojdani A, Lambert J.
Source
Immunosciences Lab., Inc., 822 S. Robertson Boulevard, Suite 312, Los Angeles, CA 90035,
USA. [email protected].
Abstract
CD4(+) effector cells, based on cytokine production, nuclear receptors and signaling
pathways, have been categorized into four subsets. T-helper-1 cells produce IFN-gamma,
TNF-beta, lymphotoxin and IL-10; T-helper-2 cells produce IL-4, IL-5, IL-10, IL-13, IL-21
and IL-31; T-helper-3, or regulatory T-cells, produce IL-10, TGF-beta and IL-35; and the
recently discovered T-helper-17 cell produces IL-17, IL-17A, IL-17F, IL-21, IL-26 and
CCL20. By producing IL-17 and other signaling molecules, Th17 contributes to the
pathogenesis of multiple autoimmune diseases including allergic inflammation, rheumatoid
arthritis, autoimmune gastritis, inflammatory bowel disease, psoriasis and multiple sclerosis.
In this article, we review the differential regulation of inflammation in different tissues with a
major emphasis on enhancement of neuroinflammation by local production of IL-17 in the
brain. By understanding the role of pathogenic factors in the induction of autoimmune
diseases by Th17 cells, CAM practitioners will be able to design CAM therapies targeting
Th17 and associated cytokine activities and signaling pathways to repair the intestinal and
blood-brain barriers for their patients with autoimmunities, in particular, those with
neuroinflammation and neurodegeneration.
Supplemental Content