Abstract
Simple SummaryExpanded, antigen-experienced CD8+ T cells are utilized in immunotherapy to treat infections and cancers. Antigen rechallenge of these cells leads to their re-expansion. The effector functions of re-expanded CD8+ T cells are critical for their therapeutic efficacy. We found that acute conditioning of the cells, before antigen rechallenge, impacts their effector function after re-expansion. Our data showed that acute pharmacological modulation of the GSK3β-mTORC axis with TWS119 or rapamycin, but not Torin1, before antigen rechallenge promotes the effector functions of re-expanded CD8+ T cells. These findings suggest that acute conditioning of the GSK3β-mTORC axis in expanded CD8+ T cells, before antigen rechallenge, can promote the therapeutic performance of re-expanded CD8+ T cells.CD8+ T cells protect against tumors and intracellular pathogens. The inflammatory cytokines IL-2, IL-15, and IL-7 are necessary for their expansion. However, elevated serum levels of these cytokines are often associated with cancer, poorer prognosis of cancer patients, and exhaustion of antigen-expanded CD8+ T cells. The impact of acute conditioning of antigen-expanded CD8+ T cells with these cytokines is unknown. Here, we generated antigen-expanded CD8+ T cells using dendritic cells and PC-3 cells. The cells were acutely (18–24 h) conditioned with IL-2 and either the GSK3β inhibitor TWS119, the mTORC1 inhibitor rapamycin, or the mTORC1/2 inhibitor Torin1, then their immediate and post-re-expansion (distal) cytokine responses after antigen rechallenge were evaluated. We found that acute IL-2 conditioning upregulated the immediate antigen-induced cytokine response of the tested cells. Following their re-expansion, however, the cells showed a decreased cytokine response. These IL-2 conditioning-mediated impacts were counteracted with TWS119 or rapamycin but not with Torin1. Our data revealed that the acute conditioning of antigen-expanded CD8+ T cells with IL-2 modulates the GSK3β-mTORC signaling axis. This modulation differentially affected the immediate and distal cytokine responses of the cells. The acute targeting of this signaling axis could, therefore, represent a novel strategy for the modulation of antigen-expanded CD8+ T cells.
Highlights
CD8+ T cells are important players in the adaptive immune system [1]
To investigate the impact of acute modulation of CD8+ T cell signaling on their immediate and post-re-expansion effector functions, we developed a novel and robust study system based on the use of allogeneic dendritic cells (DCs) and the prostate cancer cell line PC-3
To investigate the impact of the inflammatory cytokine IL-2 on antigen-expanded CD8+ T cells, we developed a novel study model, based on the combined use of mature allogeneic monocyte-derived
Summary
CD8+ T cells are important players in the adaptive immune system [1]. Antigen challenge of naive CD8+ T cells with professional antigen-presenting cells induces their proliferation and differentiation into a variety of T cell subsets [1]. The most potent growth factors of naive and antigen-expanded CD8+ T cells are the inflammatory cytokines IL-2, IL-15, and IL-7 [3]. These cytokines can be elevated during cancer, chronic inflammatory infections, and immunotherapy [4,5,6,7,8,9]. High concentrations of these cytokines are used during the ex vivo generation of T cells for adoptive cell transfer (ACT) [3,10].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
