Lymphopenia-induced lymphoproliferation drives activation of naive T cells and expansion of regulatory populations

Chemotherapy pre-conditioning is an essential component of chimeric antigen receptor transduced cell therapy. Acute lymphopenia-induced proliferation (LIP) is known to be driven primarily by homeostatic cytokines, but little is known on the underlying mechanisms in humans. We undertook phenotypic and transcriptional analysis of T cells undergoing LIP two weeks post-myeloablative autograft stem cell transplantation. Strong IL-7 signaling was reflected in downregulated IL-7R expression on all T cells, including naive cells, along with parallel increased IL-2Rα expression. Notably, activated residual naive cells expressed Fas indicating recent TCR engagement. Moreover, proportion of Ki67 + FoxP3+ Tregs was almost doubled. Transcriptional analysis revealed increased fatty acid metabolism and interferon signaling responses. In contrast, TGF-β signaling was strongly suppressed. Thus, human LIP response is characterized by cytokine and TCR-driven proliferation which drives global T cell activation but also preferentially triggers regulatory cell expansion which may limit tumor-specific immunity. These features indicate potential therapeutic opportunities to manipulate immunotherapy regimens incorporating LIP conditioning protocols.