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Pyrimidine nucleotide starvation induces a decrease in the number of effector T cells but not memory T cells

Cellular & Molecular Immunology volume 20, pages 859–860 (2023)Cite this article

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Scherer et al. investigated the influence of de novo pyrimidine nucleotide synthesis on T-cell responses after antigen stimulation, particularly on effector and memory T-cell development [1]. Their work focused on the effect of leflunomide (trade name Avara®), which is a direct inhibitor of dihydroorotate dehydrogenase (DHODH; a key enzyme in the de novo pyrimidine nucleotide pathway and located on the inner mitochondrial membrane). In this pathway, DHODH converts dihydroorotate to orotate and has been implicated in the reduction of ubiquinol to ubiquinone mediated by Complex III in the electron transport chain. The metabolic effects of DHODH inhibition are unclear [2, 3]. However, it is known to block S-phase progression by activating P53. Leflunomide was originally approved for the treatment of rheumatoid arthritis (RA) in 1998; the mechanism involves the induction of S-phase cell cycle arrest and apoptosis, inhibiting cell proliferation and self-renewal. Preclinical studies have demonstrated the therapeutic potential of leflunomide for cancer [4]. Despite the efficacy of leflunomide, the mechanism by which it targets immune cells in the treatment of RA was unknown; however, the work of Scherer and colleagues has shed new light on this mechanism.

To explore the effects of pyrimidine starvation by leflunomide on the proliferation and differentiation of effector CD8+ T cells, OT-1 T cells carrying the T-cell receptor CD8+ were transferred into naïve mice that were subsequently treated or not with leflunomide before infection. An analysis revealed that, compared to the control group mice, the mice treated with leflunomide exhibited a substantial reduction in the number of antigen-specific CD8+ T cells during the effector phase, a response that remained constant over time. The findings also suggested that the cells in the treated mice lacked a prominent contraction phase. Notwithstanding the limited expansion of CD8+ T cells in leflunomide-treated mice during infection, the memory CD8+ T cells that emerged after the initial challenge were found to be functional in a secondary challenge, and their effects were comparable to those of the control group (no leflunomide treatment). The effect of leflunomide on effector CD8+ T-cell development impaired SLEC generation, whereas the absolute number of MPECs was unaffected. Furthermore, Scherer et al. showed that patients with RA who received leflunomide and were vaccinated against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) developed memory CD4+ T cells against peptide pools that included the SARS-CoV-2 spike protein.

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References

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Funding

Funding

This work was supported in part by the Creative-Pioneering Researchers Program through Seoul National University (to H-RK); Samsung Research Funding and Incubation Center of Samsung Electronics (SRFC-TC2003-02); the Bio & Medical Technology Development Program of the National Research Foundation (NRF) & funded by the Korean government (MSIT) (2018M3A9H4055197, 2021M3A9I2080497, and 2023R1A2C1004944).

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  1. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea

    Gwanghun Kim, Hyun Mu Shin & Hang-Rae Kim

  2. Department of Anatomy & Cell Biology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea

    Gwanghun Kim & Hang-Rae Kim

  3. BK21 FOUR Biomedical Science Project, Department of Anatomy & Cell Biology, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea

    Hyun Mu Shin & Hang-Rae Kim

  4. Medical Research Institute, Seoul National University College of Medicine, Seoul, 03080, Republic of Korea

    Hyun Mu Shin & Hang-Rae Kim

  5. Wide River Institute of Immunology, Seoul National University, Hongcheon, 25159, Republic of Korea

    Hang-Rae Kim

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  1. Gwanghun Kim
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Correspondence to Hang-Rae Kim.

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Kim, G., Shin, H.M. & Kim, HR. Pyrimidine nucleotide starvation induces a decrease in the number of effector T cells but not memory T cells. Cell Mol Immunol 20, 859–860 (2023). https://doi.org/10.1038/s41423-023-01014-z

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