Role of regulatory T cells and FOXP3 in human diseases Bacchetta, Rosa, MD; Gambineri, Eleonora, MD; Roncarolo, Maria-Grazia, MD
Journal of allergy and clinical immunology,
08/2007, Letnik:
120, Številka:
2
Journal Article
Recenzirano
Immune regulation and tolerance are specific functions of the immune system, meaning at prevention or limitation of effector immune responses against inner and external insults. Regulatory T (Treg) ...cells are crucial players in this immune balance network. Research over the last 10 years has significantly contributed to characterizing Treg cell features, their mechanisms of function, and their role in human pathologies. The discovery of FOXP3 as an essential transcription factor not only for differentiation and function of naturally occurring Treg cells but also for regulation of intracellular molecules related to effector T-cell responses has provided new insights into the pathogenesis of immune-mediated diseases. Interestingly, there is increasing evidence that the individual signature of genes relevant for immune regulation definitely influences the final outcome of an immune response.
Background Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is an autoimmune genetic disorder caused by mutation of the forkhead box protein 3 gene (FOXP3) , a key ...regulator of immune tolerance. Objective We sought to provide clinical and molecular indicators that facilitate the understanding and diagnosis of IPEX syndrome. Methods In 14 unrelated affected male subjects who were given diagnoses of IPEX syndrome based on FOXP3 gene sequencing, we determined whether particular FOXP3 mutations affected FOXP3 protein expression and correlated the molecular and clinical data. Results Molecular analysis of FOXP3 in the 14 subjects revealed 13 missense and splice-site mutations, including 7 novel mutations. Enteropathy, generally associated with endocrinopathy and eczema, was reported in all patients, particularly in those carrying mutations within FOXP3 functional domains or mutations that altered protein expression. However, similar genotypes did not always result in similar phenotypes in terms of disease presentation and severity. In addition, FOXP3 protein expression did not correlate with disease severity. Conclusion Severe autoimmune enteropathy, which is often associated with increased IgE levels and eosinophilia, is the most prominent early manifestation of IPEX syndrome. Nevertheless, the disease course is variable and somewhat unpredictable. Therefore genetic analysis of FOXP3 should always be performed to ensure an accurate diagnosis, and FOXP3 protein expression analysis should not be the only diagnostic tool for IPEX syndrome.
...because of the onset of MDS, at age 9 years, he underwent hematopoietic stem cell transplant from his HLA-matched (GATA2 wild-type) brother. Cytogenetic data were described according to ...International System for Human Cytogenetic Nomenclature 2009.E3 Clinical symptoms Laboratory findings Differential diagnosis HSCT indication UTI Mild leukopenia and neutropenia Congenital/autoimmune neutropenia Chromosome 7 monosomy Aphthous stomatitis Absent monocytes and DCsLow B cells/NK cells Rheumatological diseases (ie, SLE) Â Warts Bone marrow hypocellurarity with mild dysmyelopoiesis ALPS Â Fever and reactive arthritis (Parvovirus B19 infection) Normal immunoglobulin valuesNegative autoimmune screening Bone marrow failure (TERC/TINF2) Â Localized alopecia areata Negative viral PCRs Unspecified antibody defects (but normal serum immunoglobulin levels) Â Table E1 Summary of clinical and laboratory findings, possible differential diagnosis, and indication for performing HSCT See text for more details.ALPS, Autoimmune lymphoproliferative syndrome; SLE, systemic lupus erythematosus, UTI, upper respiratory tract infection.
Background Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) is a primary immunodeficiency with autoimmunity caused by mutations in forkhead box P3 (FOXP3 ), which encodes a ...transcription factor involved in regulatory T (Treg) cell function. The mechanistic basis for how different mutations in FOXP3 cause distinct manifestations of IPEX remains unclear. Objective To determine whether 3 different point mutants of FOXP3 that cause severe or mild IPEX differ in their ability to reprogram conventional T cells into Treg cells. Methods Human CD4+ T cells were transduced with wild-type or point mutant forms of FOXP3 , and changes in cell surface marker expression, cytokine production, proliferation and suppressive capacity were assessed. Ex vivo TH 17 cells were also transduced with different forms of FOXP3 to monitor changes in IL-17 production. Results The forkhead mutant F373A failed to upregulate CD25 and CCR4, did not suppress cytokine production, and induced suppressive activity less effectively than wild-type FOXP3. In contrast, although the forkhead mutant R347H was also defective in upregulation of CD25, it suppressed the production of cytokines, conferred suppressive capacity on CD4+ T cells, and suppressed IL-17 production. F324L, a mutant outside the forkhead domain associated with mild IPEX, was equivalent to wild-type FOXP3 in all aspects tested. Conclusion Mutations in FOXP3 that cause IPEX do not uniformly abrogate the ability of FOXP3 to regulate transcription and drive the development of Treg cells. These data support the notion that factors in addition to functional changes in Treg cells, such as alterations in conventional T cells, are involved in the pathogenesis of IPEX.
The identified FOXP3 gene mutation was associated with a reduced protein expression in Treg cells (Figs E1 and E2 available in this article's Online Repository at www.jacionline.org). ...at 6 months ...of age, he received an unmanipulated, unrelated donor cord blood stem cell transplant (1 DP mismatch) with sub-myeloablative conditioning and graft-versus-host disease (GvHD) prophylaxis (see this article's Methods section and Fig E3 in the Online Repository at www.jacionline.org). Consistent with the sub-myeloablative conditioning regimen the patient has received, mixed myeloid chimerism was also observed; however, as previously reported,4-6 donor myeloid chimerism is not necessary to control the disease. ...FOXP3 protein expression by Treg cells increased over time (Fig E2).
Background Mutations in signal transducer and activator of transcription (STAT) 1 cause a broad spectrum of disease, ranging from severe viral and bacterial infections (amorphic alleles) to mild ...disseminated mycobacterial disease (hypomorphic alleles) to chronic mucocutaneous candidiasis (CMC; hypermorphic alleles). The hypermorphic mutations are also associated with arterial aneurysms, autoimmunity, and squamous cell cancers. Objective We sought to investigate the role of STAT1 gain-of-function mutations in phenotypes other than CMC. Methods We initially screened patients with CMC and autoimmunity for STAT1 mutations. We functionally characterized mutations in vitro and studied immune profiles and regulatory T (Treg) cells. After our initial case identifications, we explored 2 large cohorts of patients with wild-type forkhead box protein 3 and an immune dysregulation–polyendocrinopathy–enteropathy–X-linked (IPEX)–like phenotype for STAT1 mutations. Results We identified 5 children with polyendocrinopathy, enteropathy, and dermatitis reminiscent of IPEX syndrome; all but 1 had a variety of mucosal and disseminated fungal infections. All patients lacked forkhead box protein 3 mutations but had uniallelic STAT1 mutations (c.629 G>T, p.R210I; c.1073 T>G, p.L358W, c.796G>A; p.V266I; c.1154C>T, T385M 2 patients). STAT1 phosphorylation in response to IFN-γ, IL-6, and IL-21 was increased and prolonged. CD4+ IL-17–producing T-cell numbers were diminished. All patients had normal Treg cell percentages in the CD4+ T-cell compartment, and their function was intact in the 2 patients tested. Patients with cells available for study had normal levels of IL-2–induced STAT5 phosphorylation. Conclusions Gain-of-function mutations in STAT1 can cause an IPEX-like phenotype with normal frequency and function of Treg cells.
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