Researchers Target Altered T Cell Metabolism in SLE to Reverse Lupus Immuno-Phenotype

Patients with systemic lupus erythematosus (SLE) have abnormal T cell populations. Specifically, they have a decreased percentage of CD4⁺CD45RA⁺CCR7⁺ T_n cells and a corresponding increase in CD4⁺CD45^–CCR7⁺T_cm cells, which results in an altered T_n/T_cm profile when compared with healthy individuals. The T cells in patients with lupus also have defective interleukin-2 (IL-2) production. Research has shown that activated T cells upregulate glycolysis following activation in a manner similar to that seen in cancer cells. Thus, naive and activated CD4+ T cell subsets have distinct metabolic profiles. Typically, T cell metabolism is then regulated via the dual inhibition of glycolysis and mitochondrial metabolism.

Yiming Yin, a graduate student at the University of Florida in Gainseville, Fla., and colleagues questioned whether a defective CD4+ T cell metabolism might underlie both murine and human SLE. They published the results of their analysis of T cell metabolism and lupus in February 2015 in Science Translational Medicine. The researchers noted that several diseases can be treated by such metabolic modulators as rapamycin, N-acetylcysteine, metformin and 2-deoxy-D-glucose (2DG). They, thus, investigated whether drugs that target glycolysis and mitochondrial metabolism might be able to normalize TC CD4+ T cell functions, thereby affecting disease pathology.

The investigators began their experiments in lupus prone B6.Sle1.Sle2.Sle3 (TC) mice. They focused on these mice because their CD4+ T cells have multiple immune abnormalities that are characteristic of lupus pathogenesis. The analysis revealed that the CD4+ T cells from TC mice also show an increased expression of glycolytic genes Hif1a, Hk2, and Slc16a3. They then performed an in vitro experiment and treated the T cells from the TC mice with metformin. They found that such treatment was able to restore the defective IL-2 production.

Researchers next sought to treat the mice with metabolic modulators. To target both the glucose and mitochondrial metabolisms, they treated TC mice with a combination of metformin (Met) and 2DG (Met + 2DG). The researchers found that such a treatment was able to normalize T cell metabolism and reverse disease biomarkers. Specifically, Met + 2DG decreased the percentage of total splenic CD4+ T cells and decreased the percentage of CD69+ (T_em expression). The treated mice maintained their body weight and blood glucose.

The investigators then sought to understand the relative contribution of Met and 2DG in disease reversal. They found that the combination therapy was superior to Met or 2DG alone, which suggested to them that Met and 2DG worked synergistically to reverse the lupus phenotype. When they tested two additional mouse models of lupus (NZB/W mice and chronic graft-vs.-host disease-induced lupus), they found that, in both cases, treatment with Met + 2DG reduced CD4+ T cell metabolism and reduced the production of anti-dsDNA IgG.

“Our study provides possible mechanisms by which Met and 2DG reversed immuno-phenotypes in vivo. Met regulates cellular metabolism through complex mechanisms, including the inhibition of the mitochondrial respiratory chain complex I. Here, the Met + 2DG treatment decreased T cell mitochondrial oxygen consumption, as well as mTORC1 [mammalian target of rapamycin complex 1] signaling in both the TC and NZB/W models,” write the authors in their discussion.

They concluded their paper by suggesting that new therapies that target T cell metabolism may be useful for the treatment of SLE.

Lara C. Pullen, PhD, is a medical writer based in the Chicago area.

Reference

1. Yin Y, Choi SC, Xu Z, et al. Normalization of CD4+ T cell metabolism reverses lupus. Sci Transl Med. 2015 Feb 11;7(274):274ra18. doi: 10.1126/scitranslmed.aaa0835