| 1. |
- Leavenworth, J. W., et al.
(författare)
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Amelioration of arthritis through mobilization of peptide-specific CD8(+) regulatory T cells
- 2013
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Ingår i: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738. ; 123:3, s. 1382-1389
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Tidskriftsartikel (refereegranskat)abstract
- Current therapies to treat autoimmune disease focus mainly on downstream targets of autoimmune responses, including effector cells and cytokines. A potentially more effective approach would entail targeting autoreactive T cells that initiate the disease cascade and break self tolerance. The murine MHC class Ib molecule Qa-1b (HLA-E in humans) exhibits limited polymorphisms and binds to 2 dominant self peptides: Hsp60p216 and Qdm. We found that peptide-induced expansion of tetramer-binding CD8+ Tregs that recognize Qa-1–Hsp60p216 but not Qa-1–Qdm strongly inhibited collagen-induced arthritis, an animal model of human rheumatoid arthritis. Perforin-dependent elimination of autoreactive follicular Th (TFH) and Th17 cells by CD8+ Tregs inhibited disease development. Infusion of in vitro–expanded CD8+ Tregs increased the efficacy of methotrexate treatment and halted disease progression after clinical onset, suggesting an alternative approach to this first-line treatment. Moreover, infusion of small numbers of Qa-1–Hsp60p216–specific CD8+ Tregs resulted in robust inhibition of autoimmune arthritis, confirming the inhibitory effects of Hsp60p216 peptide immunization. These results suggest that strategies designed to expand Qa-1–restricted (HLA-E–restricted), peptide-specific CD8+ Tregs represent a promising therapeutic approach to autoimmune disorders.
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| 2. |
- Shen, E., et al.
(författare)
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Chromatin remodeling by the NuRD complex regulates development of follicular helper and regulatory T cells
- 2018
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 115:26, s. 6780-6785
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Tidskriftsartikel (refereegranskat)abstract
- Lineage commitment and differentiation into CD4(+) T cell subsets reflect an interplay between chromatin regulators and transcription factors (TF). Follicular T cell development is regulated by the Bc16 TF, which helps determine the phenotype and follicular localization of both CD4(+) follicular helper T cells (T-FH) and follicular regulatory T cells (T-FR). Here we show that Bc16-dependent control of follicular T cells is mediated by a complex formed between Bc16 and the Mi-2 beta-nucleosome-remodeling deacetylase complex (Mi-2 beta-NuRD). Formation of this complex reflects the contribution of the intracellular isoform of osteopontin (OPN-i), which acts as a scaffold to stabilize binding between Bc16 and the NuRD complex that together regulate the genetic program of both T-FH and T-FR cells. Defective assembly of the Bc16-NuRD complex distorts follicular T cell differentiation, resulting in impaired T-FR development and skewing of the T-FH lineage toward a T(H)1-like program that includes expression of Blimp1, Tbet, granzyme B, and IFN gamma. These findings define a core Bc16-directed transcriptional complex that enables CD4(+) follicular T cells to regulate the germinal center response.
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| 3. |
- Nilsson, Gisela M A, 1973, et al.
(författare)
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Two different isoforms of osteopontin modulate myelination and axonal integrity
- 2023
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Ingår i: Faseb Bioadvances. - 2573-9832. ; 5:8, s. 336-353
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Tidskriftsartikel (refereegranskat)abstract
- Abnormal myelination underlies the pathology of white matter diseases such as preterm white matter injury and multiple sclerosis. Osteopontin (OPN) has been suggested to play a role in myelination. Murine OPN mRNA is translated into a secreted isoform (sOPN) or an intracellular isoform (iOPN). Whether there is an isoform-specific involvement of OPN in myelination is unknown. Here we generated mouse models that either lacked both OPN isoforms in all cells (OPN-KO) or lacked sOPN systemically but expressed iOPN specifically in oligodendrocytes (OLs-iOPN-KI). Transcriptome analysis of isolated oligodendrocytes from the neonatal brain showed that genes and pathways related to increase of myelination and altered cell cycle control were enriched in the absence of the two OPN isoforms in OPN-KO mice compared to control mice. Accordingly, adult OPN-KO mice showed an increased axonal myelination, as revealed by transmission electron microscopy imaging, and increased expression of myelin-related proteins. In contrast, neonatal oligodendrocytes from OLs-iOPN-KI mice compared to control mice showed differential regulation of genes and pathways related to the increase of cell adhesion, motility, and vasculature development, and the decrease of axonal/neuronal development. OLs-iOPN-KI mice showed abnormal myelin formation in the early phase of myelination in young mice and signs of axonal degeneration in adulthood. These results suggest an OPN isoform-specific involvement, and a possible interplay between the isoforms, in myelination, and axonal integrity. Thus, the two isoforms of OPN need to be separately considered in therapeutic strategies targeting OPN in white matter injury and diseases.
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