Thymically derived Foxp3(+) regulatory T cells (tTregs) constitute a unique T cell lineage that is essential for maintaining immune tolerance to self and immune homeostasis. However, Foxp3 can also ...be turned on in conventional T cells as a consequence of antigen exposure in the periphery, under both non-inflammatory and inflammatory conditions. These so-called peripheral Tregs (pTregs) participate in the control of immunity at sites of inflammation, especially at the mucosal surfaces. Although numerous studies have assessed in vitro generated Tregs (termed induced or iTregs), these cells most often do not recapitulate the functional or phenotypic characteristics of in vivo generated pTregs. Thus, there are still many unanswered questions regarding the T cell receptor (TCR) repertoire and function of pTregs as well as conditions under which they are generated in vivo, and the degree to which these characteristics identify specialized features of pTregs versus features that are shared with tTregs. In this review, we summarize the current state of our understanding of pTregs and their relationship to the tTreg subset. We describe the recent discovery of unique cell surface markers and transcription factors (including Neuropilin-1 and Helios) that can be used to distinguish tTreg and pTreg subsets in vivo. Additionally, we discuss how the improved ability to distinguish these subsets provided new insights into the biology of tTregs versus pTregs and suggested differences in their function and TCR repertoire, consistent with a unique role of pTregs in certain inflammatory settings. Finally, these recent advances will be used to speculate on the role of individual Treg subsets in both tolerance and autoimmunity.
Summary
Foxp3+ T‐regulatory cells (Tregs) are primarily generated in the thymus (tTreg), but also may be generated extrathymically at peripheral sites (pTreg), or induced in cell culture (iTreg) in ...the presence of transforming growth factor β (TGFβ). A major unresolved issue is how these different populations of Tregs exert their suppressive function in vivo. We have developed novel systems in which the function of Tregs can be evaluated in vivo in normal mice. Our studies demonstrate that one prominent mechanism of action of polyclonal tTregs is to inhibit T‐effector cell trafficking to the target organ, while antigen‐specific iTregs primarily prevent T‐cell priming by acting on antigen‐presenting dendritic cells (DCs). Interleukin‐10 (IL‐10) plays an important role in the suppressive function of antigen‐specific iTregs by controlling the expression of MARCH1 and CD83 on the DC. Activated tTregs may mediate infectious tolerance by delivery of cell surface‐expressed TGFβ to naive responder T cells to generate pTregs. Manipulation of Treg function will require the ability to differentiate tTregs from pTregs and iTregs. The expression of the transcription factor Helios has proven to be a useful marker for the identification of stable tTregs in both mouse and human.
ABSTRACT In this work, a gradual solar energetic particle (SEP) event observed by multi-spacecraft has been simulated. The time profiles of SEP fluxes accelerated by an interplanetary shock in the ...three-dimensional interplanetary space are obtained by solving numerically the Fokker-Planck focused transport equation. The interplanetary shock is modeled as a moving source of energetic particles. By fitting the 1979 March 01 SEP fluxes observed by Helios 1, Helios 2, and IMP 8 with our simulations, we obtain the best parameters for the shock acceleration efficiency model. And we also find that the particle perpendicular diffusion coefficient with the level of ∼1%-3% of parallel diffusion coefficient at 1 AU should be included. The reservoir phenomenon is reproduced in the simulations, and the longitudinal gradient of SEP fluxes in the decay phase, which is observed by three spacecraft at different locations, is more sensitive to the shock acceleration efficiency parameters than that is to the perpendicular diffusion coefficient.
Helios (encoded by IKZF2), a member of the Ikaros family of transcription factors, is a zinc finger protein involved in embryogenesis and the development and regulation of the immune system. Although ...predominantly recognized for its role in the development and function of T lymphocytes, particularly the CD4+ regulatory T cells (Tregs), the expression and function of Helios extends beyond the immune system. During embryogenesis, Helios is expressed at varying levels in a wide range of tissues, making genetic variants that disrupt the function of Helios strong candidates for causing widespread immune-related and developmental abnormalities in humans. Here, we investigated two unrelated individuals with immune dysregulation combined with syndromic features including craniofacial dysmorphism, sensorineural hearing loss, and congenital abnormalities resulting from de novo heterozygous variants that alter the critical DNA-binding zinc fingers (ZF) of Helios. Proband 1 (p. Gly136_Ser191dup) had a tandem duplication of ZFs 2 and 3 in the DNA-binding domain of Helios and Proband 2 (p.Gly153Arg) had a missense variant impacting one of the key residues for specific base recognition and DNA interaction in ZF2 of Helios. Functional studies confirmed that both these variant proteins are expressed, and that they interfere with the ability of the wild-type Helios protein to perform its canonical function—repressing IL2 transcription activity—in a dominant negative manner. Our study is the first to describe dominant-negative IKZF2 variants. These variants cause a novel genetic syndrome characterized by Immunodysregulation, Craniofacial anomalies, Hearing impairment, Athelia, and Developmental delay (ICHAD syndrome).
Julian (331/32-363) wandte sich als einziger römischer Kaiser vom Christentum zurück zur alten Religion und versuchte, die Konstantinische Wende rückgängig zu machen. Dafür setzte er auch wieder ...stärker auf die imperiale römische Tradition der Sonnenverehrung. Der Hymnos auf den König Helios entfaltet in philosophischer Manier die kosmische, aber auch die politische Dimension des Helios und bietet so die theoretisch-ideologische Begründung von Julians anti-christlichen politisch-administrativen Maßnahmen, die er seit seinem Amtsantritt als Alleinherrscher 361 ergriffen hatte. Die hier vorliegende neue zweisprachige und kommentierte Ausgabe erläutert den philosophischen Kontext und Gehalt von Julians Solartheologie und beleuchtet den Text aus verschiedenen fachlichen Perspektiven philosophisch, religionswissenschaftlich, theologisch, historisch und literaturwissenschaftlich.
How does a novelist from Emesa represent through two characters, one Egyptian, the other Ethiopian, the emblematic sanctuary of Hellenism, the « navel » of the world ? Is this representation ...fictional or factual ? Is it built on intertextuality or does it correspond to something seen ? It is difficult to decide, especially since the dating of the work is uncertain. The description, in the form of ekphrasis, lays emphasis on religious ceremonies where the love of the protagonists is born. Delphi and Apollo play a central role in the plot, even if, outside Greece, their fame and their primacy are questioned, even ignored. Begun in the Delphic sanctuary, the love affair finds its consecration in Ethiopia, in Meroe, where Helios supplants Apollo.
Background: The control of auto-reactive cells is defective in rheumatoid arthritis (RA). Regulatory T (Treg) cells which play a key role in the modulation of immune responses have an impaired ...function in RA. Foxp3 is a master regulator of Treg cells which its expression is under the tight control of epigenetic mechanisms. In the current study, we analyzed the epigenetic modulation of the Foxp3 Treg-specific demethylated region (TSDR) and Helios gene expression to determine Treg cells alteration in RA patients.
Methods: We have recruited 20 newly diagnosed patients with RA and 41 healthy controls in our study. The measurement of Foxp3 and Helios gene expression was performed by the real-time PCR technique and the methylation level of TSDR was analyzed by bisulfite treatment and quantitative methylation-specific PCR (Q-MSP).
Results: We found that RA patients had significantly lower level of Foxp3 gene expression and TSDR demethylation compared to healthy subjects (P < 0.001 and P = 0.006, respectively). Inversely, the Helios gene expression was elevated significantly in RA patients group (P = 0.048). We also observed a significant correlation between Foxp3 and Helios gene expression (P = 0.016) as well as a significant correlation between FoxP3 expression and demethylation rate of TSDR (P = 0.010).
Conclusion: Our results suggested that both epigenetic modifications and Helios gene expression may have important roles in the pathogenesis of RA through their effects on Foxp3 gene expression.
CD4+ regulatory T cells lacking Helios and Eos Polak, Katarzyna; Marchal, Patricia; Taroni, Chiara ...
Biochemical and biophysical research communications,
09/2023, Letnik:
674
Journal Article
Recenzirano
Odprti dostop
The transcriptional regulators that drive regulatory T (Treg) cell development and function remain partially understood. Helios (Ikzf2) and Eos (Ikzf4) are closely-related members of the Ikaros ...family of transcription factors. They are highly expressed in CD4+ Treg cells and functionally important for Treg cell biology, as mice deficient for either Helios or Eos are susceptible to autoimmune diseases. However, it remains unknown if these factors exhibit specific or partially redundant functions in Treg cells. Here we show that mice with germline deletions of both Ikzf2 and Ikzf4 are not very different from animals with single Ikzf2 or Ikzf4 deletions. Double knockout Treg cells differentiate normally, and efficiently suppress effector T cell proliferation in vitro. Both Helios and Eos are required for optimal Foxp3 protein expression. Surprisingly, Helios and Eos regulate different, largely non-overlapping, sets of genes. Only Helios is required for proper Treg cell aging, as Helios deficiency results in reduced Treg cell frequencies in the spleen of older animals. These results indicate that Helios and Eos are required for distinct aspects of Treg cell function.
•Mice lacking both Helios and Eos have unimpaired Treg cell development.•Both Eos and Helios are required for optimal Foxp3 expression.•Age dependent increase in Treg cell frequency is dependent on Helios.•Helios and Eos control distinct transcriptional programs in Treg cells.•Helios deficient Treg cells have an activated gene expression signature.
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