Intrinsic T cell glutaminolysis promotes autoimmunity in lupus-prone mice
Seung-Chul Choi, Yong Ge, Milind V. Joshi, Damian Jimenez, Abigail Castellanos Garcia, Cassandra LaPlante, Lauren T. Padilla, Chaoyu Ma, Nu Zhang, Jeffrey C. Rathmell, Mansour Mohamadzadeh, Laurence Morel
Seung-Chul Choi, Yong Ge, Milind V. Joshi, Damian Jimenez, Abigail Castellanos Garcia, Cassandra LaPlante, Lauren T. Padilla, Chaoyu Ma, Nu Zhang, Jeffrey C. Rathmell, Mansour Mohamadzadeh, Laurence Morel
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Research Article Immunology

Intrinsic T cell glutaminolysis promotes autoimmunity in lupus-prone mice

Abstract

Glutaminolysis is enhanced in T cells of patients with lupus and in Tfh cells, a critical subset of CD4+ T cells that provide help to autoreactive B cells, in lupus mice. Glutaminolysis inhibitors reduced lupus activity in association with a decreased frequency of Th17 cells in mice. Here, we thought to determine the role of glutaminolysis in murine Tfh cells. The pharmacological inhibition of glutaminolysis with DON reduced the expression of the critical costimulatory molecule ICOS on lupus Tfh cells, in association with a reduction of autoantibody production and B cell differentiation markers. Accordingly, profound transcriptomic and metabolic changes, including a reduction of glycolysis, were induced by DON in lupus Tfh cells, whereas healthy Tfh cells showed minor changes. The T cell–specific genetic inhibition of glutaminolysis largely phenocopied the effects of DON on Tfh cells and B cells in an autoimmune genetic background with minor changes in Tfh and B cells in healthy controls. Furthermore, we showed that T cell–specific glutaminolysis inhibition impaired T-dependent humoral responses in autoimmune mice as well as their Tfh response to a viral infection. Overall, these results suggest that lupus Tfh cells have a greater intrinsic requirement of glutaminolysis for their helper functions.

Authors

Seung-Chul Choi, Yong Ge, Milind V. Joshi, Damian Jimenez, Abigail Castellanos Garcia, Cassandra LaPlante, Lauren T. Padilla, Chaoyu Ma, Nu Zhang, Jeffrey C. Rathmell, Mansour Mohamadzadeh, Laurence Morel

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Figure 8

Gls1 CD4-KO reduced CD4+ T and B cell responses to LCMV infection.

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Gls1 CD4-KO reduced CD4+ T and B cell responses to LCMV infection. Sple...
Splenic CD4+ T cells and B cells were analyzed 7 days after infection with LCMV Armstrong. (A and B) Frequency of total (A) and GP66+ (B) CD4+ T cells, with representative FACS plots on the right. (C–E) Frequency of total (C), GP66+ (D), and Ki-67+ Th1 cells (E). (F–H) Frequency of total (F), GP66+ (G), and Ki-67+ (H) Tfh cells. (I–L) Frequency of TCF1–CX3CR1+ (I), TCF1+CX3CR1+ (J), TCF1+CX3CR1– (K), and TCF1+CX3CR1– (L) GP66+ CD4+ T cells, with representative FACS plots on the right. (M) CD62L expression in the four GP66+ CD4+ T cell subsets. (N–P) Frequency of B cells (N), GC B cells (O), and plasma cells (P). Mean ± SEM, n = 3–5 compared with Šídák’s multiple or Dunnett’s (E and P) comparisons tests. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.