Abstract
The CD4+FOXP3+ regulatory T cell (Treg) subset is an indispensable mediator of immune tolerance. While high and stable expression of the transcription factor FOXP3 is considered a hallmark feature of Treg cells, our previous studies have demonstrated that the human FOXP3+ subset is functionally heterogeneous, whereby a sizeable proportion of FOXP3+ cells in healthy individuals have a diminished capacity to suppress the proliferation and cytokine production of responder cells. Notably, these non-suppressive cells are indistinguishable from suppressive Treg cells using conventional markers of human Treg. Here we investigate potential factors that underlie loss of suppressive function in human Treg cells. We show that high expression of the IL-6 family cytokine receptor subunit gp130 identifies Treg cells with reduced suppressive capacity ex vivo and in primary FOXP3+ clones. We further show that two gp130-signaling cytokines, IL-6 and IL-27, impair the suppressive capacity of human Treg cells. Finally, we show that gp130 signaling reduces the expression of the transcription factor Helios, whose expression is essential for stable Treg function. These results highlight the role of gp130 in regulating human Treg function, and suggest that modulation of gp130 signaling may serve as a potential avenue for the therapeutic manipulation of human Treg function.
Highlights
CD4+FOXP3+ regulatory T cells (Treg) play an essential role in the maintenance of tolerance to self and harmless antigens
Stable FOXP3 expression is considered a specific feature of Treg cells, it is established that human CD4+ Teff cells can express FOXP3 upon activation, making them indistinguishable from Treg cells in activation or inflammatory contexts [3, 4]
We expand clones generated from single CD4+CD25High and CD4+CD25Neg primary T cells from human Peripheral blood mononuclear cells (PBMC), and analyze their phenotypic and functional profiles at the end of a short-term activation cycle, allowing activation-induced FOXP3 expression to subside resulting in a state of immune quiescence
Summary
CD4+FOXP3+ regulatory T cells (Treg) play an essential role in the maintenance of tolerance to self and harmless antigens. Numerous studies have examined potential defects in the Treg population as underlying or contributory factors in human organspecific autoimmunity [reviewed in [2]]. While several groups reported numerical and functional defects in the Treg compartment in a number of autoimmune diseases such as multiple sclerosis (MS), type 1 diabetes (T1D), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), others have observed normal Treg frequency and function in these diseases [reviewed in [2]]. In addition to potential disease heterogeneity and methodological variations that may have contributed to the variable findings in these studies, lack of reliable human Treg cell markers is a significant limitation [2]. While a number of markers allow for the detection of highly-enriched
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
