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

Eldershaw S; Verma K; Croft W; Rai T; Kinsella Fam; Stephens C; Chen H; Nunnick J; Zuo J; Malladi R; Moss P

doi:10.1016/j.isci.2021.102164

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

iScience. 2021 Feb 7;24(3):102164. doi: 10.1016/j.isci.2021.102164. eCollection 2021 Mar 19.

Authors

Eldershaw S¹, Verma K¹, Croft W^{1

2}, Rai T¹, Kinsella Fam^{1

3}, Stephens C¹, Chen H¹, Nunnick J³, Zuo J¹, Malladi R³, Moss P^{1

2}

Affiliations

¹ Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.
² Centre for Computational Biology, University of Birmingham, Birmingham, UK.
³ Center for clinical Haematology, Queen Elizabeth Hospital, Birmingham, UK.

Abstract

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.

Keywords: Cell Biology; Immunology.

Abstract

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