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
Similar to conventional chemokine receptors,atypical chemokine receptors(ACKRs)are cell-surface receptors that possess a seven transmembrane domain structure and regulate immune responses by interacting with chemokine...Similar to conventional chemokine receptors,atypical chemokine receptors(ACKRs)are cell-surface receptors that possess a seven transmembrane domain structure and regulate immune responses by interacting with chemokines.However,ACKRs differ from conventional chemokine receptors because of their inability to couple to G proteins and therefore to transduce intracellular signals mediating leukocyte migration upon chemokine binding.Instead,ACKRs internalize,transport or scavenge chemokines,regulating their extracellular availability,and thus impacting homeostasis,inflammation and immune response.展开更多
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The work of RF is supported by the grants of the Deutsche Forschungsgemeinschaft(SFB900-B1,SFB738-B5,KFO250,FO334/5-1)the European Research Council(ERC Advanced Grant 322645)the Government of Lower Saxony(N-RENNT,BioFabrication for NIFE).
文摘Similar to conventional chemokine receptors,atypical chemokine receptors(ACKRs)are cell-surface receptors that possess a seven transmembrane domain structure and regulate immune responses by interacting with chemokines.However,ACKRs differ from conventional chemokine receptors because of their inability to couple to G proteins and therefore to transduce intracellular signals mediating leukocyte migration upon chemokine binding.Instead,ACKRs internalize,transport or scavenge chemokines,regulating their extracellular availability,and thus impacting homeostasis,inflammation and immune response.
