Inhibition of glucose metabolism selectively targets autoreactive follicular helper T cells

Abstract

Follicular helper T (TFH) cells are expanded in systemic lupus erythematosus, where they are required to produce high affinity autoantibodies. Eliminating TFH cells would, however compromise the production of protective antibodies against viral and bacterial pathogens. Here we show that inhibiting glucose metabolism results in a drastic reduction of the frequency and number of TFH cells in lupus-prone mice. However, this inhibition has little effect on the production of T-cell-dependent antibodies following immunization with an exogenous antigen or on the frequency of virus-specific TFH cells induced by infection with influenza. In contrast, glutaminolysis inhibition reduces both immunization-induced and autoimmune TFH cells and humoral responses. Solute transporter gene signature suggests different glucose and amino acid fluxes between autoimmune TFH cells and exogenous antigen-specific TFH cells. Thus, blocking glucose metabolism may provide an effective therapeutic approach to treat systemic autoimmunity by eliminating autoreactive TFH cells while preserving protective immunity against pathogens.

Immune cell metabolism in autoimmunity

“…While treatment with either metformin or 2DG alone could prevent the development of the disease [32], these results indicate that targeting cellular metabolism could be a potential therapy for lupus and other autoimmune diseases [37]. This glycolytic requirement is restricted to autoreactive Tfh cells, as Tfh cells induced by immunization with a nominal antigen or by infection with influenza virus were not affected by 2DG [26]. 1), and their expansion as well as that of GC B cells was abrogated by 2DG treatment [26].…”

“…Gln deprivation led to the differentiation of activated naïve CD4 + T cells [6] and Th1-polarized cells [94] into T reg cells. This diminished Tfh function, in both lupus-prone and non-autoimmune mice [26], indicating that it required for the development of germinal centers. Blocking glutamate oxaloacetate transaminase 1 (Got1) also altered the balance between Th17 and T reg REVIEW SERIES: TRANSLATING IMMUNOMETABOLISM cells without affecting Th1 cells [93].…”

“…These results suggest that T cell differentiation of most T cell subsets is mTOR-dependent and aberrant expression of mTOR might lead to autoimmunity. Tfh cells in the B6.Sle1.Sle2.Sle3 (TC) model of lupus show a high level of mTORC1 activation, which was reduced by the inhibition of glucose metabolism [26]. Indeed, treatment with sirolimus, an mTOR inhibitor, reduced disease activity in refractory lupus patients [25].…”

“…The combination of 2-deoxy-D-glucose (2DG), a glycolysis inhibitor, and metformin, which inhibits complex I of the mitochondrial electron transport chain [36], reversed lupus pathogenesis in mice [31]. 1), and their expansion as well as that of GC B cells was abrogated by 2DG treatment [26]. Among the subsets of T cells, Tfh cells from lupus mice are highly glycolytic (Fig.…”

“…Indeed, glutaminolysis is a major source of energy for the generation of Th17 cells [6]. Slc1a5 expression was lower in TC Tfh than in congenic non-autoimmune B6 Tfh cells [26]. Gln transporter deficiency or depletion of Gln in culture media inhibited both Th1 and Th17 differentiation [95], but blocking the conversion of Gln to glutamate preferentially suppressed Th17 over other T cell subsets [6,92].…”