Genomic profiling of T-cell activation suggests increased sensitivity of memory T cells to CD28 costimulation

Dafni A Glinos,Alan Kennedy,Gosia Trynka,Cayman Williams,Luke Jostins,Blagoje Soskic,David M Sansom

doi:10.1038/s41435-020-00118-0

Abstract

T-cell activation is a critical driver of immune responses. The CD28 costimulation is an essential regulator of CD4 T-cell responses, however, its relative importance in naive and memory T cells is not fully understood. Using different model systems, we observe that human memory T cells are more sensitive to CD28 costimulation than naive T cells. To deconvolute how the T-cell receptor (TCR) and CD28 orchestrate activation of human T cells, we stimulate cells using varying intensities of TCR and CD28 and profiled gene expression. We show that genes involved in cell cycle progression and division are CD28-driven in memory cells, but under TCR control in naive cells. We further demonstrate that T-helper differentiation and cytokine expression are controlled by CD28. Using chromatin accessibility profiling, we observe that AP1 transcriptional regulation is enriched when both TCR and CD28 are engaged, whereas open chromatin near CD28-sensitive genes is enriched for NF-kB motifs. Lastly, we show that CD28-sensitive genes are enriched in GWAS regions associated with immune diseases, implicating a role for CD28 in disease development. Our study provides important insights into the differential role of costimulation in naive and memory T-cell responses and disease susceptibility.

Highlights

The ability of T cells to respond to pathogens whilst remaining tolerant to host antigens is critical for human health
We initially modulated CD28 costimulation by titrating abatacept (CTLA4-Ig), a drug used in treating immune diseases that reduces T-cell activation by blocking costimulation
These data are in line with previous concepts, that memory T cells are less dependent on costimulation compared to naive T cells, continuing to proliferate when CD28 engagement is blocked

Summary

Introduction

The ability of T cells to respond to pathogens whilst remaining tolerant to host antigens is critical for human health. Excessive activation of memory T cells is a hallmark of many common complex immune diseases, such as. While the exact effects of the associated variants are unknown, their mapping to the non-coding regions of the genome suggests effects on gene expression regulation [7, 8]. This implies that immune disease GWAS variants could act through the modulation of the activity of costimulatory pathways.

Methods

Results

Conclusion