Transcriptomes of Effector Memory T cells undergoing lymphopenia induced proliferation

Purpose: T cells undergo intense proliferation in the setting of lymphopenia and chemotherapy pre-conditioning is therefore an essential component of CAR-T therapy. Lymphopenia-induced proliferation (LIP) is thought to be mediated primarily by homeostatic cytokines such as IL-7 and IL-15 but little is known regarding the underlying mechanisms in human subjects Methods: We undertook transcriptional analysis of CD4+ and CD8+ T cells following myeloablative autograft stem cell transplantation. Results: T cells at day 12 after transplant were undergoing intense proliferation and the proportion of naïve T cells was markedly reduced and replaced by an effector pool.The proportion of FoxP3+ regulatory cells was almost doubled by day 12 and the global effector T cell pool also displayed a transcriptional profile typical of activated regulatory cells. Transcriptional analysis further revealed intense cell cycle activation driven by fatty acid metabolism and strong signalling responses to interferon. In contrast, TGF-? signalling, a major negative regulator of T cell proliferation, was strongly suppressed Conclusions: The human LIP response is thus characterised by intense cytokine and TCR-driven proliferation which drives global T cell activation but also preferentially triggers a regulatory cell expansion which may limit induction of tumour-specific immunity. These features indicate a range of potential therapeutic opportunities to manipulate immunotherapy regimens that incorporate LIP conditioning protocols. Overall design: Total RNA profiles of Effector Memory CD8 and CD4 T cells from the peripheral blood of healthy donors and patients at Day 12 post autograft stem cell transplantation