9 research outputs found
Genomic profiling of T-cell activation suggests increased sensitivity of memory T cells to CD28 costimulation
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
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