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.
BackgroundOral immunotherapy (OIT) is an emerging treatment for cow’s milk protein (CMP) allergy in children. The mechanisms driving tolerance following OIT are not well understood. Regulatory T cells (TREG) cells are key inhibitors of allergic responses and promoters of allergen-specific tolerance. In an exploratory study, we sought to detect induction of allergen-specific TREG in a cohort of subjects undergoing OIT.MethodsPediatric patients with a history of allergic reaction to cow’s milk and a positive Skin Pick Test (SPT) and/or CMP-specific IgE >0.35 kU, as well as a positive oral challenge to CMP underwent OIT with escalating doses of milk and were followed for up to 6 months. At specific milestones during the dose escalation and maintenance phases, casein-specific CD4+ T cells were expanded from patient blood by culturing unfractionated PBMCs with casein in vitro. The CD4+ T cell phenotypes were quantified by flow cytometry.ResultsOur culture system induced activated casein-specific FOXP3+Helios+ TREG cells and FOXP3- TEFF cells, discriminated by expression of CD137 (4-1BB) and CD154 (CD40L) respectively. The frequency of casein-specific TREG cells increased significantly with escalating doses of milk during OIT while casein-specific TEFF cell frequencies remained constant. Moreover, expanded casein-specific TREG cells expressed higher levels of FOXP3 compared to polyclonal TREG cells, suggesting a more robust TREG phenotype. The induction of casein-specific TREG cells increased with successful CMP desensitization and correlated with increased frequencies of casein-specific Th1 cells among OIT subjects. The level of casein-specific TREG cells negatively correlated with the time required to reach the maintenance phase of desensitization.ConclusionsOverall, effective CMP-OIT successfully promoted the expansion of casein-specific, functionally-stable FOXP3+ TREG cells while mitigating Th2 responses in children receiving OIT. Our exploratory study proposes that an in vitro TREG response to casein may correlate with the time to reach maintenance in CMP-OIT.
The immune system requires a homeostatic equilibrium among the mechanisms that assure self‐tolerance, those that control the capacity to mount life‐long immunity to pathogenic microbes and those that attenuate effector mechanisms from inducing immune pathology. There are multiple processes in place to ensure that healthy immune regulation and FOXP3 + T regulatory (Treg) cells are thought to be the major players. Treg cells exercise their regulatory role through various contact‐dependent and ‐independent mechanisms, and FOXP3 is the master regulator of their various functions such as inhibiting T effector (Teff) cell proliferation and inflammatory cytokine production. Various autoimmune diseases such as IPEX occur when Treg‐cell function or numbers are abrogated. Although there is evidence that supports the involvement of Treg cells in the development of autoimmune disease, there are inconsistencies in the literature owing to the lack of Treg‐cell‐specific markers. Key Concepts The immune system employs multiple tolerance mechanisms to maintain immune homeostasis. Multiple specialised regulatory cells exist, FOXP3+ T regulatory (Treg) cells being one of the major players in the maintenance of immune tolerance. FOXP3 is the master transcription factor of Treg cells, controlling Treg‐cell phenotype and suppressive functions. Autoimmune diseases such as IPEX arise when Treg cells are defective or lacking, which can be due to mutations at the Foxp3 gene locus. Multiple markers are currently being used to study the Treg‐cell population; however, these markers are not specific to Treg cells and therefore are the cause of inconsistencies in the literature on the topic of Treg‐cell function in health and disease. Disturbances in FOXP3+ Treg‐cell development, homeostasis and/or function are thought to occur in many autoimmune and chronic inflammatory diseases in humans.
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