Inhibition of glucose metabolism selectively targets autoreactive follicular helper T cells

• Published in: Nature communications Vol. 9; no. 1; pp. 4369 - 13
• Main Authors: Choi, Seung-Chul, Titov, Anton A., Abboud, Georges, Seay, Howard R., Brusko, Todd M., Roopenian, Derry C., Salek-Ardakani, Shahram, Morel, Laurence
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.10.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/31; 14/19; 38/61; 38/77; 631/250/2152/1566/1618; 631/250/38; 64/60; Amino acids; Amino Acids - metabolism; Animals; Antibodies; Antigens; Autoantibodies; Autoantibodies - metabolism; Autoimmune diseases; Autoimmunity; Autoimmunity - physiology; Chronic conditions; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Fluxes; Glucose; Glucose - metabolism; Humanities and Social Sciences; Immunity; Immunization; Influenza; Inhibition; Lupus; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - metabolism; Lymphocytes; Lymphocytes T; Metabolism; Mice; multidisciplinary; Pathogens; Science; Science (multidisciplinary); Systemic lupus erythematosus; T-Lymphocytes, Helper-Inducer - metabolism; Viruses
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-06686-0

Follicular helper T (T FH ) cells are expanded in systemic lupus erythematosus, where they are required to produce high affinity autoantibodies. Eliminating T FH 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 T FH 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 T FH cells induced by infection with influenza. In contrast, glutaminolysis inhibition reduces both immunization-induced and autoimmune T FH cells and humoral responses. Solute transporter gene signature suggests different glucose and amino acid fluxes between autoimmune T FH cells and exogenous antigen-specific T FH cells. Thus, blocking glucose metabolism may provide an effective therapeutic approach to treat systemic autoimmunity by eliminating autoreactive T FH cells while preserving protective immunity against pathogens. T cell functions depend on distinct metabolic fluxes. Here the authors show different metabolic requirements of humoral responses to self versus microbial antigens: while glucose is dispensable for antiviral Tfh and antibody responses, it is essential to mount these responses against autoantigens.