Crispri-Mediated Knock-Down of Prdm1/Blimp1 Programs Central Memory Differentiation in Ex Vivo-Expanded Human T Cells Publisher



Azadbakht M¹ ; Sayadmanesh A² ; Nazer N³ ; Ahmadi A⁴ ; Hemmati S^{2, 5} ; Mohammadzade H³ ; Ebrahimi M² ; Baharvand H^{2, 6} ; Khalaj B³ ; Aghamaali MR¹ ; Basiri M²
Source: BioImpacts Published:2022

Abstract

Introduction: B lymphocyte-induced maturation protein 1 (BLIMP1) encoded by the positive regulatory domain 1 gene (PRDM1), is a key regulator in T cell differentiation in mouse models. BLIMP1-deficiency results in a lower effector phenotype and a higher memory phenotype. Methods: In this study, we aimed to determine the role of transcription factor BLIMP1 in human T cell differentiation. Specifically, we investigated the role of BLIMP1 in memory differentiation and exhaustion of human T cells. We used CRISPR interference (CRISPRi) to knock-down BLIMP1 and investigated the differential expressions of T cell memory and exhaustion markers in BLIMP1-deficient T cells in comparison with BLIMP1-sufficient ex vivo expanded human T cells. Results: BLIMP1-deficiency caused an increase in central memory (CM) T cells and a decrease in effector memory (EM) T cells. There was a decrease in the amount of TIM3 exhaustion marker expression in BLIMP1-deficient T cells; however, there was an increase in PD1 exhaustion marker expression in BLIMP1-deficient T cells compared with BLIMP1-sufficient T cells. Conclusion: Our study provides the first functional evidence of the impact of BLIMP1 on the regulation of human T cell memory and exhaustion phenotype. These findings suggest that BLIMP1 may be a promising target to improve the immune response in adoptive T cell therapy settings. © 2022 The Author(s).