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• W2030254840 abstract "Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a primary immunodeficiency with severe autoimmunity caused by mutations in the forkhead box protein 3 gene (FOXP3). FOXP3 encodes a transcription factor critical for the function of naturally occurring regulatory T (Treg) cells, which are devoted to tolerance maintenance. Impairment of Treg cells is the main pathogenic mechanism underlying IPEX syndrome.1Gambineri E. Perroni L. Passerini L. Bianchi L. Doglioni C. Meschi F. et al.Clinical and molecular profile of a new series of patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: inconsistent correlation between forkhead box protein 3 expression and disease severity.J Allergy Clin Immunol. 2008; 122 (e1): 1105-1112Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar However, increasing evidence suggests that FOXP3 might also impinge effector T (Teff) cells.2Allan S.E. Crome S.Q. Crellin N.K. Passerini L. Steiner T.S. Bacchetta R. et al.Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production.Int Immunol. 2007; 19: 345-354Crossref PubMed Scopus (692) Google Scholar Indeed, FOXP3 inhibits TH17 cell differentiation and IL-17 production,3Crome S.Q. Wang A.Y. Levings M.K. Translational mini-review series on Th17 cells: function and regulation of human T helper 17 cells in health and disease.Clin Exp Immunol. 2010; 159: 109-119Crossref PubMed Scopus (219) Google Scholar and we reasoned that in patients with IPEX syndrome, in addition to loss of suppressive function, augmented TH17 responses might be responsible for autoimmunity. We therefore investigated the presence of IL-17–producing T cells both in patients with new-onset IPEX (age <2 years; within 9 months from onset; n = 6), and in long-term patients (age >12 years; n = 4), who were undergoing immunosuppression. The present cohort was also heterogeneous in terms of site of the mutation (see Table E1 in this article’s Online Repository at www.jacionline.org). After in vitro short-term expansion (12-20 days) in the presence of immobilized anti-CD3 (10 μg/mL) and soluble anti-CD28 (1 μg/mL) mAbs and recombinant human IL-2 (100 U/mL), patients’ CD4+ T cells displayed significantly increased IL-17A and decreased IFN-γ production compared with that seen in cells of healthy donors (HDs; Fig 1, A and B), whereas IL-10 production was comparable with that seen in control T-cell lines (data not shown). In addition, activated PBMCs from patients with new-onset disease (n = 3) showed high IL-17A production (range in patients, 57-1493 pg/mL; range in HDs, 0-80 pg/mL; results were normalized to 106 cells/mL), whereas the production of TH1 (IFN-γ) and TH2 (IL-5) cytokines was in the same range as that seen in HDs (not shown). In long-term patients overall cytokine production by PBMCs was low, but production of IL-17A was augmented in the presence of recombinant human IL-2 (fold increase ranging from 1.4 to 37, data not shown). Treatment with multidrug immunosuppression is likely to alter the T-cell capacity to produce cytokines, including IL-17, but prompt restoration in the presence of exogenous IL-2 suggests that TH17 cells are present also in long-term patients, although they are hyporesponsive because of immunosuppression. Analogously, we found increased expression of the TH17 cell–specific transcription factor retinoic acid–related orphan receptor variant 2 (RORC2) in ex vivo CD4+ T cells of patients with new-onset disease compared with that seen in age-matched HDs (Fig 1, C). This increase was specific because it was not paralleled by high expression of the TH1 cell transcription factor T-bet and was not due to a higher frequency of memory/effector CD45RO+ T cells in patients (not shown). In long-term patients RORC2 expression was not significantly augmented compared with that seen in HDs (data not shown). Overall, these findings indicate that TH17 cells are present in the peripheral blood of patients with IPEX syndrome, regardless of the type or site of mutation, especially at early onset, whereas TH1 and TH2 cytokine levels are comparable with those seen in HDs. This sheds light on previous controversial data on IL-17 production in patients with IPEX syndrome, which either describe high IL-17 production at onset in 1 patient together with increased TH1 and TH2 cytokine levels4d’Hennezel E. Ben-Shoshan M. Ochs H.D. Torgerson T.R. Russell L.J. Lejtenyi C. et al.FOXP3 forkhead domain mutation and regulatory T cells in the IPEX syndrome.N Engl J Med. 2009; 361: 1710-1713Crossref PubMed Scopus (93) Google Scholar or report IL-17 production within normal ranges in patients undergoing immunosuppression.5Moes N. Rieux-Laucat F. Begue B. Verdier J. Neven B. Patey N. et al.Reduced expression of FOXP3 and regulatory T-cell function in severe forms of early-onset autoimmune enteropathy.Gastroenterology. 2010; 139: 770-778Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar Although Treg cells were initially thought to bear a stable phenotype, recent advances in the field revealed new features for this lineage. The possibility that specific subsets of Treg cells can diverge from a regulatory fate and acquire proinflammatory properties, including the capacity to produce TH17 cytokines, has been proposed as a physiologic mechanism to allow efficient response to pathogens or to restrain detrimental immune regulation.6Hori S. Developmental plasticity of Foxp3+ regulatory T cells.Curr Opin Immunol. 2010; 22: 575-582Crossref PubMed Scopus (64) Google Scholar On the other hand, it has been suggested that in murine models Treg cells are capable of acquiring Teff cell functions and might become autoreactive, although the latter phenomenon is still controversial.6Hori S. Developmental plasticity of Foxp3+ regulatory T cells.Curr Opin Immunol. 2010; 22: 575-582Crossref PubMed Scopus (64) Google Scholar In this context IPEX syndrome could serve as a sensible model to investigate Treg cell plasticity based on the hypothesis that Treg cells undergo thymic development but experience peripheral conversion from a regulatory to an effector (ie, IL-17–producing) phenotype in the presence of FOXP3 mutations. We found that T cells epigenetically imprinted as Treg cells, as measured by means of analysis of the Treg cell–specific demethylated region,7Wieczorek G. Asemissen A. Model F. Turbachova I. Floess S. Liebenberg V. et al.Quantitative DNA methylation analysis of FOXP3 as a new method for counting regulatory T cells in peripheral blood and solid tissue.Cancer Res. 2009; 69: 599-608Crossref PubMed Scopus (266) Google Scholar were indeed present in peripheral blood of patients at levels comparable with those seen in HDs (Fig 1, D), but FOXP3-expressing T cells were randomly distributed among CCR6+CD161+ and CD161− subpopulations or even more enriched in the CD161+ subset. On the contrary, in HDs FOXP3+ Treg cells were mainly comprised in the CD4+CCR6+CD161− T-cell population (Fig 1, E). Therefore in patients with IPEX, CCR6+CD161+ T cells, which also include TH17 cells, contained more FOXP3+ T cells than their counterpart from HDs (P = .02 vs HDs, Mann Whitney U test). These data demonstrate that (1) although dysfunctional, circulating putative Treg cells are present in patients with IPEX syndrome, thus indicating that wild-type FOXP3 is not necessary for thymic differentiation of Treg cells in human subjects, and that (2) FOXP3-mutated Treg cells cosegregate with the CCR6+CD161+ T-cell subset, which also includes TH17 cells, strongly suggesting their peripheral conversion from suppressor to IL-17–producing cells. Interestingly, levels of IL-6 and IL-23, cytokines described to favor human TH17 cell differentiation and expansion,3Crome S.Q. Wang A.Y. Levings M.K. Translational mini-review series on Th17 cells: function and regulation of human T helper 17 cells in health and disease.Clin Exp Immunol. 2010; 159: 109-119Crossref PubMed Scopus (219) Google Scholar were significantly increased in the sera of patients with IPEX syndrome compared with that seen in HDs (Fig 1, F), whereas levels of IL-1β were not (data not shown). In addition, in the presence of IL-1β and IL-6, T-cell clones generated from CD4+CD25bright T cells of patients upregulated IL-17A production, whereas IL-17A production by activated HD Treg cells was low or negative and did not consistently increase in the presence of inflammatory cytokines (Fig 1, G). On the other hand, IL-17 production by HD Treg cells was specifically induced on FOXP3 knockdown by FOXP3-specific small-interfering RNA (LV-siRNA-FOXP3)8Amendola M. Passerini L. Pucci F. Gentner B. Bacchetta R. Naldini L. Regulated and multiple miRNA and siRNA delivery into primary cells by a lentiviral platform.Mol Ther. 2009; 17: 1039-1052Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar in CD4+CD25bright Treg cell–derived lines (18.5 ± 9.4–fold increase vs LV-siRNA-control, n = 5), confirming that Treg cell stability is maintained by expression of wild-type FOXP3 (Fig 1, H). Overall, these results indicate that FOXP3-mutated Treg cells are prone to produce IL-17 and further suggest that in the absence of functional FOXP3 and in inflammatory conditions, Treg cells in patients with IPEX syndrome can be reprogrammed to produce IL-17A. Whether the presence of FOXP3 mutations favors de novo generation of IL-17–producing Teff cells remains to be clarified. In conclusion, we provide evidence of increased frequency of IL-17–producing T cells in patients with IPEX syndrome. This phenomenon might be sustained, at least in part, by inflammation-driven conversion of dysfunctional Treg cells unable to properly regulate IL-17 production. Taking into account that a significant proportion of Treg cells are self-antigen specific,9Hsieh C.S. Liang Y. Tyznik A.J. Self S.G. Liggitt D. Rudensky A.Y. Recognition of the peripheral self by naturally arising CD25+ CD4+ T cell receptors.Immunity. 2004; 21: 267-277Abstract Full Text Full Text PDF PubMed Scopus (591) Google Scholar we propose that in patients with IPEX syndrome, FOXP3-mutated TH17-converted Treg cells might directly contribute to the autoimmune damage seen in the target organs. Therefore studies to demonstrate the self-antigen specificity and pathogenicity of such cells should be pursued. Thus therapies for the restoration of Treg cell function might not be sufficient to control the disease unless in combination with approaches aimed at inhibiting the TH17 shift of potentially autoreactive FOXP3-mutated Treg cells. We thank the members of the Italian Study Group of IPEX (www.ipexconsortium.org) and the patients’ families for their participation in this study. We thank M. K. Levings and G. Fousteri for critical reading of this manuscript. We also thank C. Sartirana for technical support. Table E1Summary of the clinical, immunologic, and mutation details of patients with IPEXPatient no.FOXP3 mutationAge (2011)Age at onsetEnteropathyEndocrinopathySkin diseaseOtherTherapy3∗Patients studied before 2 years of age.IVS1+2T>G5 yNeonatalSevere diarrhea with VAIDDMMild eczemaHepatitis/sepsisHLAid BMT†Patients’ samples used for this study were collected before transplantation.7∗Patients studied before 2 years of age.IVS8+4A>G9 yNeonatalSevere diarrhea with VAIDDMSevere eczemaHepatitisIS (multiple drugs)8∗Patients studied before 2 years of age.p.P339A—NeonatalSevere diarrhea with VAIDDM—Autoimmune hepatitis/AEA/FT hepatosplenomegalyIS (multiple drugs)9p.R347H15 yNeonatalSevere diarrhea with VAIDDMMild eczemaHepatitis/thrombocytopenia/Coombs negative anemia/food allergy/FTIS (low steroids)11p.A384T16 yNeonatalSevere diarrhea with eosinophilic infiltration without VAIDDM thyroiditisSevere eczema/alopeciaAEA/interstitial pneumonia/FTIS (multiple drugs)12∗Patients studied before 2 years of age.p.F373A9 yNeonatalSevere diarrhea with VAIDDMEczema—HLAid BMT†Patients’ samples used for this study were collected before transplantation.14p.L242P15 y4 moSevere diarrhea with VA—Mild eczemaSepsis/nephropathyIS (multiple drugs)17∗Patients studied before 2 years of age.p.I346T3 yNeonatalSevere diarrhea without VA—Severe seborrhoeic dermatitisMRSA sepsis/Candida species CVL infectionCB-URD HSCT†Patients’ samples used for this study were collected before transplantation.18∗Patients studied before 2 years of age.AATAAA>AATGAA8 yNeonatalSevere diarrhea with VA—Seborrhoeic dermatitisHypotoniaCB-URD HSCT†Patients’ samples used for this study were collected before transplantation.20IVS7+2del28 y5 moSevere diarrhea with VA—EczemaThrombocytopenia/arthritis/sepsis/bronchitisIS (multiple drugs)AEA, Autoimmune hemolytic anemia; BMT, bone marrow transplantation; CB-URD, cord blood–unrelated donor; CVL, central venous line; FT, failure to thrive; HLAid, HLA identical; HSCT, hematopoietic stem cell transplantation; IDDM, insulin-dependent diabetes mellitus; IS, immunosuppression; MRSA, methicillin-resistant Staphylococcus aureus; VA, villous atrophy.∗ Patients studied before 2 years of age.† Patients’ samples used for this study were collected before transplantation. Open table in a new tab AEA, Autoimmune hemolytic anemia; BMT, bone marrow transplantation; CB-URD, cord blood–unrelated donor; CVL, central venous line; FT, failure to thrive; HLAid, HLA identical; HSCT, hematopoietic stem cell transplantation; IDDM, insulin-dependent diabetes mellitus; IS, immunosuppression; MRSA, methicillin-resistant Staphylococcus aureus; VA, villous atrophy." @default.
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• W2030254840 title "Forkhead box protein 3 (FOXP3) mutations lead to increased TH17 cell numbers and regulatory T-cell instability" @default.
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