Browsing by Author "Lightman, Shivana M."

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    CD8+ T cell metabolic flexibility elicited by CD28-ARS2 axis-driven alternative splicing of PKM supports antitumor immunity
    (Springer Nature, 2024) Holling, G. Aaron; Chavel, Colin A.; Sharda, Anand P.; Lieberman, Mackenzie M.; James, Caitlin M.; Lightman, Shivana M.; Tong, Jason H.; Qiao, Guanxi; Emmons, Tiffany R.; Giridharan, Thejaswini; Hou, Shengqi; Intlekofer, Andrew M.; Higashi, Richard M.; Fan, Teresa W. M.; Lane, Andrew N.; Eng, Kevin H.; Segal, Brahm H.; Repasky, Elizabeth A.; Lee, Kelvin P.; Olejniczak, Scott H.; Medicine, School of Medicine
    Metabolic flexibility has emerged as a critical determinant of CD8+ T-cell antitumor activity, yet the mechanisms driving the metabolic flexibility of T cells have not been determined. In this study, we investigated the influence of the nuclear cap-binding complex (CBC) adaptor protein ARS2 on mature T cells. In doing so, we discovered a novel signaling axis that endows activated CD8+ T cells with flexibility of glucose catabolism. ARS2 upregulation driven by CD28 signaling reinforced splicing factor recruitment to pre-mRNAs and affected approximately one-third of T-cell activation-induced alternative splicing events. Among these effects, the CD28-ARS2 axis suppressed the expression of the M1 isoform of pyruvate kinase in favor of PKM2, a key determinant of CD8+ T-cell glucose utilization, interferon gamma production, and antitumor effector function. Importantly, PKM alternative splicing occurred independently of CD28-driven PI3K pathway activation, revealing a novel means by which costimulation reprograms glucose metabolism in CD8+ T cells.
  • Thumbnail Image
    Item
    Indoleamine 2,3-dioxygenase 1 is essential for sustaining durable antibody responses
    (Elsevier, 2021) Lightman, Shivana M.; Peresie, Jennifer L.; Carlson, Louise M.; Holling, G. Aaron; Honikel, Mackenzie M.; Chavel, Colin A.; Nemeth, Michael J.; Olejniczak, Scott H.; Lee, Kelvin P.; Medicine, School of Medicine
    Humoral immunity is essential for protection against pathogens, emphasized by the prevention of 2-3 million deaths worldwide annually by childhood immunizations. Long-term protective immunity is dependent on the continual production of neutralizing antibodies by the subset of long-lived plasma cells (LLPCs). LLPCs are not intrinsically long-lived, but require interaction with LLPC niche stromal cells for survival. However, it remains unclear which and how these interactions sustain LLPC survival and long-term humoral immunity. We now have found that the immunosuppressive enzyme indoleamine 2,3- dioxygenase 1 (IDO1) is required to sustain antibody responses and LLPC survival. Activation of IDO1 occurs upon the engagement of CD80/CD86 on the niche dendritic cells by CD28 on LLPC. Kynurenine, the product of IDO1 catabolism, activates the aryl hydrocarbon receptor in LLPC, reinforcing CD28 expression and survival signaling. These findings expand the immune function of IDO1 and uncover a novel pathway for sustaining LLPC survival and humoral immunity.