A Genetic Model Reveals Biological Features of Neonatal CD4 Helper Cells Undergone Homeostasis in Mice.

Lei Lei,Cangang Zhang,Baojun Zhang,Huiqiang Zheng,Yujing Zou,Anjun Jiao,Xin Wang,Dan Zhang,Xiaofeng Yang,Jinli Wang,Xingzhe Zhang,Chenming Sun,Hang Yang,Yanhong Su,Haiyan Liu,Jiahui Zhang,Lin Shi,Xiaobo Zhou

doi:10.3389/fcell.2021.659744

Abstract

CD4+ T cells are essential for regulating effective immune response to pathogens and immune balance. Recent studies have demonstrated the unique features of T cells in neonate mice, such as more sensitive to antigen response and preference toward T helper 2 (Th2) response and regulatory T cells (Tregs) differentiation. However, the biological characteristics of neonatal age-derived CD4+ T cells following homeostasis remain unclear. Here we utilized a lineage tracing model of TCRδCreERR26ZsGreen to mark neonatal- and adult-derived CD4+ T cells followed by a combination analysis of activation, proliferation, survival, and differentiation. Our results showed that neonatal CD4+ T cells had higher capacity of activation, proliferation, apoptosis, and differentiation toward Th2 and T helper 17 (Th17) lineages, accompanied by a reduced potential for T helper 1 (Th1), T helper 9 (Th9), and Treg lineages. In contrast, tracked neonatal CD4+ T cells exhibited similar characters of above-mentioned of tracked adult cells in adult mice. Therefore, our data support a natural requirement for CD4+ T cells to acquire fully-equipped functional potentials of adult cells.

Highlights

In adults, CD4+ T helper cells play a pivotal role in adaptive immunity including activation of innate cells, helping B cells to produce antibodies, and generation of CD8+ cytotoxic T cells (Luckheeram et al, 2012)
In order to investigate the effect of homeostatic process on biological characteristics of neonatal CD4+ T cells in vivo, we utilized the TCRδCreERR26ZsGreen mouse model described in the previous study (Zhang et al, 2016) to track CD4+ T cells generated at the neonatal age in adult mice
We used a well-established lineage-tracing model to track neonatal CD4+ T cells to characterize their phenotypes under the steady state condition, as well as the potential of activation, survival, and T helper cell differentiation upon T cell receptor (TCR) stimulation

Summary

Introduction

CD4+ T helper cells play a pivotal role in adaptive immunity including activation of innate cells, helping B cells to produce antibodies, and generation of CD8+ cytotoxic T cells (Luckheeram et al, 2012). Characterizing Neonatal CD4 T Cells in Adults response of CD4+ T cells can lead to the occurrence of various autoimmune diseases (Pawlak et al, 2020). Under specific cytokine conditions and activation of intracellular signals, naïve CD4+ T cells are capable to differentiate into different subsets of Th1, Th2, Th9, and Th17 cells, producing inflammatory cytokines such as interferon-gamma (IFN-γ), interleukin-4 (IL4), interleukin-9 (IL-9), and interleukin-17 (IL-17) to mediate immune responses (Ruterbusch et al, 2020; Yan and Richmond, 2020). Naïve CD4+ T cells are able to develop into natural Treg cells (nTreg) in the thymus and differentiate into induced regulatory T cells (iTreg) in the presence of T cell receptor (TCR) and transforming growth factor beta (TGFβ) stimulation to maintain immune balance, preventing the occurrence of autoimmune diseases (Caza and Landas, 2015). The distinct transcriptome or epigenetic landscape allows neonate T cells to respond more strongly self-antigens or foreign antigens (Palin et al, 2013; Rudd, 2020)

Methods

Results

Conclusion