Journal article
Myelin-reactive CD8 + T cells influence conventional dendritic cell subsets towards a mature and regulatory phenotype in experimental autoimmune encephalomyelitis
Journal of neuroinflammation, Vol.22(1), 54
02/28/2025
DOI: 10.1186/s12974-025-03377-8
PMCID: PMC11869544
PMID: 40022134
Abstract
Multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system, is modeled in mice as experimental autoimmune encephalomyelitis (EAE). While CD4
T cells, primarily Th1 and Th17 subsets, drive disease pathogenesis, the exact function of CD8
T cells remains unclear. We previously demonstrated that adoptively transferred myelin-reactive CD8
T cells (PLP-CD8) prevent EAE induction and suppress ongoing disease through the engagement of MHC Class-I in recipient mice. Here, we show that PLP-CD8 induce regulatory changes in both subsets of conventional dendritic cells (cDC1 and CD11b
cDC) in vivo and in vitro. Adoptively transferred PLP-CD8 promoted both cDC subsets to adopt a mature and regulatory phenotype with an anti-inflammatory cytokine profile and a reduced capacity to support CD4
T cell proliferation. In vitro, PLP-CD8 induced similar phenotypic changes in both cDC subsets in an antigen-specific, dose-dependent manner. PLP-CD8 directly interacted with cDC1 and indirectly influenced CD11b
cDC through paracrine signaling. Notably, direct interaction with PLP-CD8 had detrimental effects on CD11b
cDC. Single-cell RNA sequencing revealed upregulation of key immunoregulatory genes, such as Foxo3, in both cDC subsets with enrichment of pathways involved in immune regulation and T cell differentiation. Our study highlights a novel mechanism in which myelin-reactive CD8
T cells directly interact with cDC1 and modulate CD11b
cDC through paracrine mechanisms to induce mature, regulatory dendritic cells, which leads to inhibited CD4
T cell responses and reduced EAE pathogenesis.
Details
- Title: Subtitle
- Myelin-reactive CD8 + T cells influence conventional dendritic cell subsets towards a mature and regulatory phenotype in experimental autoimmune encephalomyelitis
- Creators
- Mohit Upadhye - University of Iowa Health CareConnor R Wilhelm - University of IowaKai J Rogers - University of IowaChakrapani Vemulawada - Iowa City Veterans Affairs Medical Center, Iowa City, IA, 52246, USANicholas Borcherding - Washington University in St. LouisAlexander W Boyden - Iowa City VA Medical CenterKevin L Legge - University of IowaNitin J Karandikar - University of Iowa Health Care
- Resource Type
- Journal article
- Publication Details
- Journal of neuroinflammation, Vol.22(1), 54
- DOI
- 10.1186/s12974-025-03377-8
- PMID
- 40022134
- PMCID
- PMC11869544
- NLM abbreviation
- J Neuroinflammation
- ISSN
- 1742-2094
- eISSN
- 1742-2094
- Publisher
- BMC
- Grant note
- I01BX003677 / U.S. Department of Veterans Affairs I01 BX003677 / BLRD VA
- Language
- English
- Date published
- 02/28/2025
- Academic Unit
- Dermatology; Microbiology and Immunology; Pathology
- Record Identifier
- 9984797818402771
Metrics
12 Record Views