Mohammad Azadbakht
1 
, Ali Sayadmanesh
2, Naghme Nazer
3, Amirhossein Ahmadi
4, Sara Hemmati
2,5, Hoda Mohammadzade
3, Marzieh Ebrahimi
2, Hossein Baharvand
2,6, Babak Khalaj
3, Mahmoud Reza Aghamaali
1* , Mohsen Basiri
2* 1 Department of Biology, Faculty of Science, University of Guilan, Rasht, Iran
2 Department of Stem Cell and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
3 Department of Electrical Engineering, Sharif University of Technology, Tehran, Iran
4 Department of Biology, Faculty of Science, Persian Gulf University, Bushehr, Iran
5 School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
6 Department of Developmental Biology, University of Science and Culture, Tehran, Iran
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.