Inhibition of glucose metabolism selectively targets autoreactive follicular helper T cells

Seung-Chul Choi,Howard R Seay,Georges Abboud,Anton A Titov,Shahram Salek-Ardakani,Laurence Morel,Derry C Roopenian,Todd M Brusko

doi:10.1038/s41467-018-06686-0

Seung-Chul Choi, Howard R Seay + Show 6 more

Open Access

https://doi.org/10.1038/s41467-018-06686-0

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Journal: Nature Communications	Publication Date: Oct 22, 2018
Citations: 100	License type: open-access

Affiliation: University of Florida, Jackson Laboratory

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.

Highlights

Follicular helper T (TFH) cells are expanded in systemic lupus erythematosus, where they are required to produce high affinity autoantibodies
Similar results were obtained in young TC mice before the production of anti-dsDNA IgG (Supplementary Fig. 1a-d), indicating that CD4+ T cell activation and the expansion of TEM and TFH CD4+ T cells precedes the manifestation of autoimmunity. mTOR complex 1 (mTORC1) activity measured by phosphorylation of ribosomal protein S6 was increased in total TC CD4+ T cells[20]
High mTOR expression by TC TFH cells was confirmed by histology (Fig. 1e and Supplementary Fig. 1g): TC CD4+ T cells inside germinal center (GC) showed abundant mTOR staining as compared to B6 CD4+ T cells, which expressed mTOR in the T cell zone

Summary

Introduction

Follicular helper T (TFH) cells are expanded in systemic lupus erythematosus, where they are required to produce high affinity autoantibodies. We show that inhibiting glucose metabolism results in a drastic reduction of the frequency and number of TFH cells in lupus-prone mice. 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. Deoxyglucose (2DG) and the mitochondrial electron transport chain with metformin normalizes T cell metabolism and reverses autoimmune pathology[20] These findings were confirmed in NZB/W F1 and B6.lpr mice, two other models of lupus[20,21]. The frequency and number of TFH cells as well as GC B cells were normalized by this dual treatment, suggesting the autoreactive expansion of TFH cells was dependent on either glycolysis or mitochondrial metabolism, or a combination of the two

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