Abstract
The immunopathogenesis of multiple sclerosis (MS) depend on the expansion of specific inflammatory T cell subsets, which are key effectors of tissue damage and demyelination. Emerging studies evidence that a reprogramming of T cell metabolism may occur in MS, thus the identification of stimulatory molecules and associated signaling pathways coordinating the metabolic processes that amplify T cell inflammation in MS is pivotal. Here, we characterized the involvement of the cluster of differentiation (CD)28 and associated signaling mediators in the modulation of the metabolic programs regulating pro‐inflammatory T cell functions in relapsing‐remitting MS (RRMS) patients. We show that CD28 up‐regulates glycolysis independent of the T cell receptor (TCR) engagement by promoting the increase of c‐myc and the glucose transporter, Glut1, in RRMS CD4+ T cells. The increase of glycolysis induced by CD28 was important for the expression of inflammatory cytokines related to T helper (Th)17 cells, as demonstrated by the strong inhibition exerted by impairing the glycolytic pathway. Finally, we identified the class 1A phosphatidylinositol 3‐kinase (PI3K) as the critical signaling mediator of CD28 that regulates cell metabolism and amplify specific inflammatory T cell phenotypes in MS.
| Original language | English |
|---|---|
| Article number | 2926 |
| Journal | International Journal of Molecular Sciences |
| Volume | 20 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - Jun 2 2019 |
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Keywords
- CD28
- Class 1A PI3K
- C‐myc
- Glycolysis
- Inflammation
- Multiple sclerosis
- Th17 cells
ASJC Scopus subject areas
- Catalysis
- Molecular Biology
- Spectroscopy
- Computer Science Applications
- Physical and Theoretical Chemistry
- Organic Chemistry
- Inorganic Chemistry
Cite this
Cd28 autonomous signaling up‐regulates c‐myc expression and promotes glycolysis enabling inflammatory t cell responses in multiple sclerosis. / Kunk, Martina; Sambucci, Manolo; Ruggieri, Serena; Amormino, Carola; Tortorella, Carla; Gasperini, Claudio; Battistini, Luca; Tuosto, Loretta.
In: International Journal of Molecular Sciences, Vol. 20, No. 12, 2926, 02.06.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cd28 autonomous signaling up‐regulates c‐myc expression and promotes glycolysis enabling inflammatory t cell responses in multiple sclerosis
AU - Kunk, Martina
AU - Sambucci, Manolo
AU - Ruggieri, Serena
AU - Amormino, Carola
AU - Tortorella, Carla
AU - Gasperini, Claudio
AU - Battistini, Luca
AU - Tuosto, Loretta
PY - 2019/6/2
Y1 - 2019/6/2
N2 - The immunopathogenesis of multiple sclerosis (MS) depend on the expansion of specific inflammatory T cell subsets, which are key effectors of tissue damage and demyelination. Emerging studies evidence that a reprogramming of T cell metabolism may occur in MS, thus the identification of stimulatory molecules and associated signaling pathways coordinating the metabolic processes that amplify T cell inflammation in MS is pivotal. Here, we characterized the involvement of the cluster of differentiation (CD)28 and associated signaling mediators in the modulation of the metabolic programs regulating pro‐inflammatory T cell functions in relapsing‐remitting MS (RRMS) patients. We show that CD28 up‐regulates glycolysis independent of the T cell receptor (TCR) engagement by promoting the increase of c‐myc and the glucose transporter, Glut1, in RRMS CD4+ T cells. The increase of glycolysis induced by CD28 was important for the expression of inflammatory cytokines related to T helper (Th)17 cells, as demonstrated by the strong inhibition exerted by impairing the glycolytic pathway. Finally, we identified the class 1A phosphatidylinositol 3‐kinase (PI3K) as the critical signaling mediator of CD28 that regulates cell metabolism and amplify specific inflammatory T cell phenotypes in MS.
AB - The immunopathogenesis of multiple sclerosis (MS) depend on the expansion of specific inflammatory T cell subsets, which are key effectors of tissue damage and demyelination. Emerging studies evidence that a reprogramming of T cell metabolism may occur in MS, thus the identification of stimulatory molecules and associated signaling pathways coordinating the metabolic processes that amplify T cell inflammation in MS is pivotal. Here, we characterized the involvement of the cluster of differentiation (CD)28 and associated signaling mediators in the modulation of the metabolic programs regulating pro‐inflammatory T cell functions in relapsing‐remitting MS (RRMS) patients. We show that CD28 up‐regulates glycolysis independent of the T cell receptor (TCR) engagement by promoting the increase of c‐myc and the glucose transporter, Glut1, in RRMS CD4+ T cells. The increase of glycolysis induced by CD28 was important for the expression of inflammatory cytokines related to T helper (Th)17 cells, as demonstrated by the strong inhibition exerted by impairing the glycolytic pathway. Finally, we identified the class 1A phosphatidylinositol 3‐kinase (PI3K) as the critical signaling mediator of CD28 that regulates cell metabolism and amplify specific inflammatory T cell phenotypes in MS.
KW - CD28
KW - Class 1A PI3K
KW - C‐myc
KW - Glycolysis
KW - Inflammation
KW - Multiple sclerosis
KW - Th17 cells
UR - http://www.scopus.com/inward/record.url?scp=85073769184&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85073769184&partnerID=8YFLogxK
U2 - 10.3390/ijms20122926
DO - 10.3390/ijms20122926
M3 - Article
C2 - 31208018
AN - SCOPUS:85073769184
VL - 20
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1661-6596
IS - 12
M1 - 2926
ER -