Steady-state memory-phenotype conventional CD4 + T cells exacerbate autoimmune neuroinflammation in a bystander manner via the Bhlhe40/GM-CSF axis.
Min-Ji ChoHong-Gyun LeeJae-Won YoonGil-Ran KimJa-Hyun KooReshma TanejaBrian T EdelsonYou Jeong LeeJe-Min ChoiPublished in: Experimental & molecular medicine (2023)
Memory-phenotype (MP) CD4 + T cells are a substantial population of conventional T cells that exist in steady-state mice, yet their immunological roles in autoimmune disease remain unclear. In this work, we unveil a unique phenotype of MP CD4 + T cells determined by analyzing single-cell transcriptomic data and T cell receptor (TCR) repertoires. We found that steady-state MP CD4 + T cells in the spleen were composed of heterogeneous effector subpopulations and existed regardless of germ and food antigen exposure. Distinct subpopulations of MP CD4 + T cells were specifically activated by IL-1 family cytokines and STAT activators, revealing that the cells exerted TCR-independent bystander effector functions similar to innate lymphoid cells. In particular, CCR6 high subpopulation of MP CD4 + T cells were major responders to IL-23 and IL-1β without MOG 35-55 antigen reactivity, which gave them pathogenic Th17 characteristics and allowed them to contribute to autoimmune encephalomyelitis. We identified that Bhlhe40 in CCR6 high MP CD4 + T cells as a key regulator of GM-CSF expression through IL-23 and IL-1β signaling, contributing to central nervous system (CNS) pathology in experimental autoimmune encephalomyelitis. Collectively, our findings reveal the clearly distinct effector-like heterogeneity of MP CD4 + T cells in the steady state and indicate that CCR6 high MP CD4 + T cells exacerbate autoimmune neuroinflammation via the Bhlhe40/GM-CSF axis in a bystander manner.
Keyphrases
- regulatory t cells
- single cell
- dendritic cells
- induced apoptosis
- multiple sclerosis
- rna seq
- cell cycle arrest
- electronic health record
- cerebrospinal fluid
- type diabetes
- poor prognosis
- big data
- cell proliferation
- transcription factor
- binding protein
- immune response
- cell death
- signaling pathway
- machine learning
- type iii
- blood brain barrier
- adipose tissue
- inflammatory response
- data analysis
- gene expression
- pi k akt
- skeletal muscle
- embryonic stem cells