An In-Vitro Study of the Expansion and Transcriptomics of CD4+ and CD8+ Naïve and Memory T Cells Stimulated by IL-2, IL-7 and IL-15

Brooks Hopkins; Justin Fisher; Meiping Chang; Xiaoyan Tang; Zhimei Du; William J Kelly; Zuyi Huang

doi:10.3390/cells11101701

An In-Vitro Study of the Expansion and Transcriptomics of CD⁴⁺ and CD⁸⁺ Naïve and Memory T Cells Stimulated by IL-2, IL-7 and IL-15

Cells. 2022 May 20;11(10):1701. doi: 10.3390/cells11101701.

Authors

Brooks Hopkins¹, Justin Fisher¹, Meiping Chang², Xiaoyan Tang², Zhimei Du², William J Kelly¹, Zuyi Huang¹

Affiliations

¹ Department of Chemical and Biological Engineering, Villanova University, PA 19341, USA.
² Process Cell Sciences, Biologics Process R&D, Merck & Co., Inc., Kenilworth, NJ 07033, USA.

Abstract

The growth of T cells ex vivo for the purpose of T cell therapies is a rate-limiting step in the overall process for cancer patients to achieve remission. Growing T cells is a fiscally-, time-, and resource-intensive process. Cytokines have been shown to accelerate the growth of T cells, specifically IL-2, IL-7, and IL-15. Here a design of experiments was conducted to optimize the growth rate of different naïve and memory T cell subsets using combinations of cytokines. Mathematical models were developed to study the impact of IL-2, IL-7, and IL-15 on the growth of T cells. The results show that CD⁴⁺ and CD⁸⁺ naïve T cells grew effectively using moderate IL-2 and IL-7 in combination, and IL-7, respectively. CD⁴⁺ and CD⁸⁺ memory cells favored moderate IL-2 and IL-15 in combination and moderate IL-7 and IL-15 in combination, respectively. A statistically significant interaction was observed between IL-2 and IL-7 in the growth data of CD⁴⁺ naïve T cells, while the interaction between IL-7 and IL-15 was found for CD⁸⁺ naïve T cells. The important genes and related signaling pathways and metabolic reactions were identified from the RNA sequencing data for each of the four subsets stimulated by each of the three cytokines. This systematic investigation lays the groundwork for studying other T cell subsets.

Keywords: IL-15; IL-2; IL-7; RNA-sequencing; T cell subsets; T cell therapy; fuzzy-model.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Cells, Cultured
Cytokines
Humans
Immunologic Memory
Interleukin-15* / pharmacology
Interleukin-2 / pharmacology
Interleukin-7* / pharmacology
Memory T Cells
Transcriptome

Substances

Cytokines
Interleukin-15
Interleukin-2
Interleukin-7

Grants and funding

This research was performed under a Project Award Agreement from the National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL) and financial assistance award 70NANB17H002 from the U.S. Department of Commerce, National Institute of Standards and Technology.