Monocarboxylate transporter MCT1 is a target for immunosuppression

Abstract

Current immunosuppressive therapies act on T lymphocytes by modulation of cytokine production, modulation of signaling pathways or by inhibition of the enzymes of nucleotide biosynthesis. We have identified a previously unknown series of immunomodulatory compounds that potently inhibit human and rat T lymphocyte proliferation in vitro and in vivo in immune-mediated animal models of disease, acting by a novel mechanism. Here we identify the target of these compounds, the monocarboxylate transporter MCT1 (SLC16A1), using a strategy of photoaffinity labeling and proteomic characterization. We show that inhibition of MCT1 during T lymphocyte activation results in selective and profound inhibition of the extremely rapid phase of T cell division essential for an effective immune response. MCT1 activity, however, is not required for many stages of lymphocyte activation, such as cytokine production, or for most normal physiological functions. By pursuing a chemistry-led target identification strategy, we have discovered that MCT1 is a previously unknown target for immunosuppressive therapy and have uncovered an unsuspected role for MCT1 in immune biology.

The effect of Monocarboxylate Transporter (MCT1) inhibitor, AR-C117977 on accelerated rejection of cardiac grafts in pre-sensitised rats and concordant xenotransplantation

“…The dependence of activated T-lymphocytes on aerobic glycolysis (the Warburg effect) has now been established [12] but the metabolic processes required for B-lymphocyte activation and function have not been widely investigated although increased glucose metabolism after activation has been shown [13]. Our study provides evidence that MCT blockade can affect the function of B-lymphocytes in vitro and in vivo in addition to causing immunosuppression via inhibition of T-lymphocyte proliferation as we have previously described [4]. These data are consistent with a previous report of the effect of an MCT inhibitor on rat B-lymphocytes in vitro [14].…”

“…Mainly, they control the transport of monocarboxylates such as lactate across the cell membrane. They play a functional role in T-cell activation and by inhibiting the MCT1 transporter, the immunological response is reduced [4].…”

“…By inhibiting MCT1, we could induce and maintain long-term graft survival in both heart and non-vascularised transplantation models in rat with limited signs of toxicity [4][5][6][7][8]. The rejection is initiated by preexisting humoral immunity and manifests minutes after transplantation.…”

Impact of Minocycline on Extracellular Matrix Metalloproteinase Inducer, a Factor Implicated in Multiple Sclerosis Immunopathogenesis

“…Accumulating evidence supports functional roles for EMMPRIN during T cell activation and proliferation (5-7), migration (8,9), adhesion (10,11), and invasion (12,13), all steps important in the pathogenesis of MS as well as other immunological diseases (1). Although it is unclear how all these mechanisms connect, it is supported by the identification of several EMMPRIN-interacting proteins that correspond to these functions such as monocarboxylate transporters (MCTs) (14,15), integrins (16), CD98 (17), cyclophilins (18), and EMMPRIN itself (1,19). Treatment with anti-EMMPRIN Abs reduced EAE clinical severity, the number of perivascular cuffs, and MMP activity (12,20).…”

“…Indeed, just as EMMPRIN levels were downregulated in the minocycline-treated EAE spleens compared with EAE spleens without treatment (Fig. 6D), so were the levels of MCT-1 [involved in energy metabolism and the ability for T cells to rapidly divide (14,15,43)], CD98 and b1-integrin [implicated in adhesion (1,44)] and the MMP-9/TIMP-1 ratio (an indicator for MMP activity as TIMP-1 is a tissue inhibitor of metalloproteinases). In contrast, CD44, another molecule involved in adhesion (1) was upregulated in the presence of minocycline (Fig.…”