Table 2.
Identified CD4+ T-cell drug targets for autoimmune diseases.
| Disease | Gene | Experimental evidence relevant to CD4+ T cells and autoimmune diseases |
|---|---|---|
| RA | Lanosterol synthase (LSS) | Inhibition of lanosterol synthase (LSS) might decrease the endogenous cholesterol that may lead to impact cell division97. |
| 4-aminobutyrate aminotransferase (ABAT) | GABA downregulates inflammatory response in a mouse model of RA42; inhibition of ABAT might increase GABA16. | |
| Nicotinamide phosphoribosyltransferase (NAMPT) | Nampt inhibition reduces demyelination and disability in EAE56), lack of NAMPT expression affect T-cell development98. | |
| Farnesyl pyrophosphate synthase (FDPS) | Inhibition of FDPS inhibits T-cell cytokine production99. | |
| Squalene monooxygenase (SQLE) | Increased membrane cholesterol in T cells leads to an inflammatory response100. | |
| Farnesyl-diphosphate farnesyltransferase (FDFT1) | No support | |
| Bifunctional epoxide hydrolase 2 (EPHX2) | Inhibition of EPHX2 pre-clinically evaluated as a drug target for IBD58. | |
| 2-oxoglutarate dehydrogenase (OGDH) | No support | |
| Catalase (CAT) | Protect T cells against oxidative stress101. | |
| Citrate synthase (CS) | Inhibition of citrate synthase leads to a reduction in citrate, leading to reduced proliferation102. | |
| Pyruvate dehydrogenase E1 component subunit beta (PDHB) | No inhibition of CD4+ T-cell proliferation under treatment with drug ethyl-pyruvate (This study) | |
| Catechol O-methyltransferase (COMT) | Reduced CD4+ T-cell proliferation when inhibited using drug entacapone (This study) | |
| 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) | No inhibition of CD4+ T-cell proliferation under treatment with drug quercetin (This study) | |
| Superoxide dismutase [Mn], mitochondrial (SOD2) | Loss of SOD2 increased superoxide, and defective T-cell development62. | |
| Dihydroorotate dehydrogenase (DHODH) | Explored as a potential drug target for RA43 and MS103. | |
| Alpha-glucosidase (GAA) | No support | |
| Acetyl-CoA acetyltransferase, mitochondrial (ACAT1) | Target of sulfasalazine that is anti-inflammatory indicated for the treatment of ulcerative colitis and rheumatoid arthritis50. | |
| MS | Carnitine O-palmitoyltransferase 2 (CPT2) | Reduced CD4+ T-cell proliferation when inhibited using drug perhexiline (This study) |
| Catalase (CAT) | Protect T cells against oxidative stress101. | |
| ATP synthase subunit alpha (ATP5F1A) | No inhibition of CD4+ T-cell proliferation under treatment with drug quercetin (This study) | |
| ATP synthase subunit beta (ATP5F1B) | No inhibition of CD4+ T-cell proliferation under treatment with drug quercetin (This study) | |
| ATP synthase F1 subunit gamma (ATP5F1C) | No inhibition of CD4+ T-cell proliferation under treatment with drug quercetin (This study) | |
| Ornithine decarboxylase (ODC1) | No inhibition of CD4+ T-cell proliferation under treatment with drug DFMO (This study) | |
| MP cyclohydrolase (ATIC) | No inhibition of CD4+ T-cell proliferation under treatment with drug pemetrexed(This study) | |
| ATP synthase subunit delta (ATP5F1D) | No support | |
| ATP synthase F(0) complex subunit B1 (ATP5PB) | No support | |
| Alcohol dehydrogenase class-3 (ADH5) | No inhibition of CD4+ T-cell proliferation under treatment with compound N6022 (This study) | |
| Dihydropyrimidine dehydrogenase (DPYD) | Reduced CD4+ T-cell proliferation when inhibited using drug perhexiline (This study) | |
| Isocitrate dehydrogenase (IDH2) | Knockdown of IDHl or IDH2 reduces IL-17 producing cells (Patent WO2017123808A1)104. | |
| Glutathione reductase (GSR) | Inhibition of GSH de novo synthesis reduces the pathological progression of EAE44. | |
| 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) | Potential target for autoimmune diseases105. | |
| Farnesyl-diphosphate farnesyltransferase (FDFT1) | No support | |
| Dihydrofolate reductase (DHFR) | Low dose methotrexate (inhibitor of DHFR) found effective for MS, RA, and Crohn’s disease45. | |
| Pyruvate kinase (PKM) | Potential target to regulate inflammation59. | |
| Phosphoribosylglycinamide formyltransferase (GART) | No inhibition of CD4+ T-cell proliferation under treatment with drug pemetrexed (This study) | |
| 4-aminobutyrate aminotransferase (ABAT) | GABA downregulates inflammatory response in a mouse model of RA42; inhibition of ABAT might increase GABA16. | |
| Lanosterol synthase (LSS) | Inhibition of lanosterol synthase (LSS) might decrease the endogenous cholesterol, leading to impact cell division97. | |
| Fatty acid synthase (FASN) | Fatty acid synthase linked to the pathogenicity of Th17 cells106. | |
| Phosphoribosyl pyrophosphate amidotransferase (PPAT) | Knockdown of CAD and PPAT promotes regulatory CD4+ T cells107. | |
| Purine nucleoside phosphorylase (PNP) | inhibition leads to T-cell suppression108. | |
| Citrate synthase (CS) | Increased citrate in MS patients109. | |
| ADP/ATP translocase 3 (SLC25A6) | No support | |
| Carbamoyl-phosphate synthetase 2 (CAD) | Knockdown of CAD and PPAT promotes regulatory CD4+ T cells107. | |
| Squalene monooxygenase (SQLE) | Increased membrane cholesterol in T cells leads to an inflammatory response100. | |
| PBC | Nicotinamide phosphoribosyltransferase (NAMPT) | Nampt inhibition reduces demyelination and disability in EAE56, lack of NAMPT expression affect T-cell development98. |
| Inosine triphosphate pyrophosphatase (ITPA) | No support | |
| Adenosine kinase (ADK) | No support | |
| Long-chain-fatty-acid–CoA ligase 3 (ACSL3) | Reduced CD4+ T-cell proliferation when inhibited using drug EPA (This study) | |
| Thymidine phosphorylase (TYMP) | No support | |
| S-adenosylmethionine decarboxylase proenzyme (AMD1) | No support | |
| Adenine phosphoribosyltransferase (APRT) | No support | |
| Alcohol dehydrogenase class-3 (ADH5) | No support | |
| Catechol O-methyltransferase (COMT) | Reduced CD4+ T-cell proliferation when inhibited using drug entacapone (This study) | |
| Bifunctional epoxide hydrolase 2 (EPHX2) | Inhibition of EPHX2 pre-clinically evaluated as drug target for IBD58. | |
| 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) | No inhibition of CD4+ T-cell proliferation under treatment with drug quercetin (This study) | |
| Fatty acid synthase (FASN) | Fatty acid synthase linked to the pathogenicity of Th17 cells106. | |
| Beta-galactosidase (GLB1) | No support | |
| Phosphatidylglycerophosphatase and protein-tyrosine phosphatase 1 (PTPMT1) | No support | |
| Adenosine deaminase (ADA) | ADA is a potential target for the treatment of inflammatory disorders110. | |
| Lactoylglutathione lyase (GLO1) | No support | |
| Glucose-6-phosphate 1-dehydrogenase (G6PD) | No support | |
| Hypoxanthine-guanine phosphoribosyltransferase (HPRT1) | No support | |
| Alpha-glucosidase (GAA) | No support | |
| Solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3) | Glut3 expressed in differentiated cells and resting equals to glut137. | |
| Multidrug resistance-associated protein 1 (ABCC1) | No support | |
| Thioredoxin reductase 1 (TXNRD1) | Essential for DNA synthesis during T-cell metabolic reprogramming and proliferation111. | |
| Superoxide dismutase (SOD1) | No support | |
| ATP-citrate synthase (ACLY) | Inactivation of ACLY reduces IL-2-promoted CD4+ T-cell growth112. |