Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder that is thought to be mediated by autoreactive T lymphocytes that find their way into the central nervous system (CNS). The patholog...Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder that is thought to be mediated by autoreactive T lymphocytes that find their way into the central nervous system (CNS). The pathological mechanism of MS is still being elucidated but it involves complex interactions between infiltrating immune cells and resi- dent glial cells within the CNS that culminate into strong neuroinflammation and axonal damage.展开更多
Intestinal Foxp3+regulatory T cell(Treg)subsets are crucial players in tolerance to microbiota-derived and food-borne antigens,and compelling evidence suggests that the intestinal microbiota modulates their generation...Intestinal Foxp3+regulatory T cell(Treg)subsets are crucial players in tolerance to microbiota-derived and food-borne antigens,and compelling evidence suggests that the intestinal microbiota modulates their generation,functional specialization,and maintenance.Selected bacterial species and microbiota-derived metabolites,such as short-chain fatty acids(SCFAs),have been reported to promote Treg homeostasis in the intestinal lamina propria.Furthermore,gut-draining mesenteric lymph nodes(mLNs)are particularly efficient sites for the generation of peripherally induced Tregs(pTregs).Despite this knowledge,the direct role of the microbiota and their metabolites in the early stages of pTreg induction within mLNs is not fully elucidated.Here,using an adoptive transfer-based pTreg induction system,we demonstrate that neither transfer of a dysbiotic microbiota nor dietary SCFA supplementation modulated the pTreg induction capacity of mLNs.Even mice housed under germ-free(GF)conditions displayed equivalent pTreg induction within mLNs.Further molecular characterization of these de novo induced pTregs from mLNs by dissection of their transcriptomes and accessible chromatin regions revealed that the microbiota indeed has a limited impact and does not contribute to the initialization of the Treg-specific epigenetic landscape.Overall,our data suggest that the microbiota is dispensable for the early stages of pTreg induction within mLNs.展开更多
Signaling via interleukin-2 receptor(IL-2R)is a requisite for regulatory T(Treg)cell identity and function.However,it is not completely understood to what degree IL-2R signaling is required for Treg cell homeostasis,l...Signaling via interleukin-2 receptor(IL-2R)is a requisite for regulatory T(Treg)cell identity and function.However,it is not completely understood to what degree IL-2R signaling is required for Treg cell homeostasis,lineage stability and function in both resting and inflammatory conditions.Here,we characterized a spontaneous mutant mouse strain endowed with a hypomorphic Tyr129His variant of CD25,theα-chain of IL-2R,which resulted in diminished receptor expression and reduced IL-2R signaling.Under noninflammatory conditions,Cd25Y129H mice harbored substantially lower numbers of peripheral Treg cells with stable Foxp3 expression that prevented the development of spontaneous autoimmune disease.In contrast,Cd25^(Y^(129H))Treg cells failed to efficiently induce immune suppression and lost lineage commitment in a T-cell transfer colitis model,indicating that unimpaired IL-2R signaling is critical for Treg cell function in inflammatory environments.Moreover,single-cell RNA sequencing of Treg cells revealed that impaired IL-2R signaling profoundly affected the balance of central and effector Treg cell subsets.Thus,partial loss of IL-2R signaling differentially interferes with the maintenance,heterogeneity,and suppressive function of the Treg cell pool.展开更多
The vast majority of Foxp3^(+)regulatory T cells(Tregs)are generated in the thymus,and several factors,such as cytokines and unique thymic antigen-presenting cells,are known to contribute to the development of these t...The vast majority of Foxp3^(+)regulatory T cells(Tregs)are generated in the thymus,and several factors,such as cytokines and unique thymic antigen-presenting cells,are known to contribute to the development of these thymus-derived Tregs(tTregs).Here,we report the existence of a specific subset of Foxp3^(+)Tregs within the thymus that is characterized by the expression of IL-1R2,which is a decoy receptor for the inflammatory cytokine IL-1.Detailed flow cytometric analysis of the thymocytes from Foxp3^(hCD2)xRAG1^(GFP) reporter mice revealed that the IL-1R2^(+)Tregs are mainly RAG1^(GFP-)and CCR6^(+)CCR7^(-),demonstrating that these Tregs are recirculating cells entering the thymus from the periphery and that they have an activated phenotype.In the spleen,the majority of IL-1R2^(+)Tregs express neuropilin-1(Nrp-1)and Helios,suggesting a thymic origin for these Tregs.Interestingly,among all tissues studied,the highest frequency of IL-1R2^(+)Tregs was observed in the thymus,indicating preferential recruitment of this Treg subset by the thymus.Using fetal thymic organ cultures(FTOCs),we demonstrated that increased concentrations of exogenous IL-1β blocked intrathymic Treg development resulting in a decreased frequency of CD25^(+)Foxp3^(+)tTregs and an accumulation of CD25^(+)Foxp3^(-)Treg precursors.Interestingly,the addition of IL-1R2^(+)Tregs,but not IL-1R2^(+)Tregs,to reaggregated thymic organ cultures(RTOCs)abrogated the IL-1β-mediated blockade,demonstrating that these recirculating IL-1R2^(+)Tregs can quench IL-1 signaling in the thymus and thereby maintain thymic Treg development even under inflammatory conditions.展开更多
基金supported by the Helmholtz-Gemeinschaft,“Zukunft-sthema”Immunology and inflammation”(ZT-0027)supported by the Pertermax-Müller-Stiftung and the Niedersachsen Research Network on Neuroinfectiology(N-RENNT)of the Ministry of Science and Culture of Lower Saxony
文摘Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disorder that is thought to be mediated by autoreactive T lymphocytes that find their way into the central nervous system (CNS). The pathological mechanism of MS is still being elucidated but it involves complex interactions between infiltrating immune cells and resi- dent glial cells within the CNS that culminate into strong neuroinflammation and axonal damage.
基金supported by the Helmholtz-Gemeinschaft(Zukunftsthema“Aging and Metabolic Reprogramming”,ZT-0026)the Ministry for Science and Culture of Lower Saxony(research consortium COALITION)the Deutsche Forschungsgemeinschaft(SPP1656,PE 2840/1-1,and Germany’s Excellence Strategy-EXC 2155“RESIST”-Project ID 39087428).
文摘Intestinal Foxp3+regulatory T cell(Treg)subsets are crucial players in tolerance to microbiota-derived and food-borne antigens,and compelling evidence suggests that the intestinal microbiota modulates their generation,functional specialization,and maintenance.Selected bacterial species and microbiota-derived metabolites,such as short-chain fatty acids(SCFAs),have been reported to promote Treg homeostasis in the intestinal lamina propria.Furthermore,gut-draining mesenteric lymph nodes(mLNs)are particularly efficient sites for the generation of peripherally induced Tregs(pTregs).Despite this knowledge,the direct role of the microbiota and their metabolites in the early stages of pTreg induction within mLNs is not fully elucidated.Here,using an adoptive transfer-based pTreg induction system,we demonstrate that neither transfer of a dysbiotic microbiota nor dietary SCFA supplementation modulated the pTreg induction capacity of mLNs.Even mice housed under germ-free(GF)conditions displayed equivalent pTreg induction within mLNs.Further molecular characterization of these de novo induced pTregs from mLNs by dissection of their transcriptomes and accessible chromatin regions revealed that the microbiota indeed has a limited impact and does not contribute to the initialization of the Treg-specific epigenetic landscape.Overall,our data suggest that the microbiota is dispensable for the early stages of pTreg induction within mLNs.
基金This work was supported by the ERC Advanced Grants 322645,SFB900-B1,and SFB738-B5(all to R.F.)and SFB738-C7(to J.H.).We gratefully acknowledge the assistance of Dr.Matthias Ballmaier of the Cell Sorting Core Facility of Hannover Medical School for superb service.The cDNA and HTO libraries used in this publication were sequenced at the Research Core Unit Genomics at Hannover Medical School.We thank Svetlana Piter for providing excellent animal care and Natalio Garbi(IEI Bonn)for providing Ccr2^(−/−)(Ccr2^(tm1Mae))mice.
文摘Signaling via interleukin-2 receptor(IL-2R)is a requisite for regulatory T(Treg)cell identity and function.However,it is not completely understood to what degree IL-2R signaling is required for Treg cell homeostasis,lineage stability and function in both resting and inflammatory conditions.Here,we characterized a spontaneous mutant mouse strain endowed with a hypomorphic Tyr129His variant of CD25,theα-chain of IL-2R,which resulted in diminished receptor expression and reduced IL-2R signaling.Under noninflammatory conditions,Cd25Y129H mice harbored substantially lower numbers of peripheral Treg cells with stable Foxp3 expression that prevented the development of spontaneous autoimmune disease.In contrast,Cd25^(Y^(129H))Treg cells failed to efficiently induce immune suppression and lost lineage commitment in a T-cell transfer colitis model,indicating that unimpaired IL-2R signaling is critical for Treg cell function in inflammatory environments.Moreover,single-cell RNA sequencing of Treg cells revealed that impaired IL-2R signaling profoundly affected the balance of central and effector Treg cell subsets.Thus,partial loss of IL-2R signaling differentially interferes with the maintenance,heterogeneity,and suppressive function of the Treg cell pool.
基金supported by the CRC 738(to J.H.),CRC/TR 128(to A.W.)and CRC/TRR 221(to M.F.)of the German Research Foundationby grants from the European Research Council(ERC-CoG,#648145 REGiREG)to M.F.Y.E.supported by Ph.D scholarship program no.57129429 of the German Academic Exchange Service(DAAD).
文摘The vast majority of Foxp3^(+)regulatory T cells(Tregs)are generated in the thymus,and several factors,such as cytokines and unique thymic antigen-presenting cells,are known to contribute to the development of these thymus-derived Tregs(tTregs).Here,we report the existence of a specific subset of Foxp3^(+)Tregs within the thymus that is characterized by the expression of IL-1R2,which is a decoy receptor for the inflammatory cytokine IL-1.Detailed flow cytometric analysis of the thymocytes from Foxp3^(hCD2)xRAG1^(GFP) reporter mice revealed that the IL-1R2^(+)Tregs are mainly RAG1^(GFP-)and CCR6^(+)CCR7^(-),demonstrating that these Tregs are recirculating cells entering the thymus from the periphery and that they have an activated phenotype.In the spleen,the majority of IL-1R2^(+)Tregs express neuropilin-1(Nrp-1)and Helios,suggesting a thymic origin for these Tregs.Interestingly,among all tissues studied,the highest frequency of IL-1R2^(+)Tregs was observed in the thymus,indicating preferential recruitment of this Treg subset by the thymus.Using fetal thymic organ cultures(FTOCs),we demonstrated that increased concentrations of exogenous IL-1β blocked intrathymic Treg development resulting in a decreased frequency of CD25^(+)Foxp3^(+)tTregs and an accumulation of CD25^(+)Foxp3^(-)Treg precursors.Interestingly,the addition of IL-1R2^(+)Tregs,but not IL-1R2^(+)Tregs,to reaggregated thymic organ cultures(RTOCs)abrogated the IL-1β-mediated blockade,demonstrating that these recirculating IL-1R2^(+)Tregs can quench IL-1 signaling in the thymus and thereby maintain thymic Treg development even under inflammatory conditions.