Inflammatory Cytokines That Enhance Antigen Responsiveness of Naive CD8+ T Lymphocytes Modulate Chromatin Accessibility of Genes Impacted by Antigen Stimulation

Naive CD8(+) T lymphocytes exposed to certain inflammatory cytokines undergo proliferation and display increased sensitivity to antigens. Such 'cytokine priming' can promote the activation of potentially autoreactive and antitumor CD8(+) T cells by weak tissue antigens and tumor antigens. To elucidate the molecular mechanisms of cytokine priming, naive PMEL-1 TCR transgenic CD8(+) T lymphocytes were stimulated with IL-15 and IL-21, and chromatin accessibility was assessed using the assay for transposase-accessible chromatin (ATAC) sequencing. PMEL-1 cells stimulated by the cognate antigenic peptide mgp100(25-33) served as controls. Cytokine-primed cells showed a limited number of opening and closing chromatin accessibility peaks compared to antigen-stimulated cells. However, the ATACseq peaks in cytokine-primed cells substantially overlapped with those of antigen-stimulated cells and mapped to several genes implicated in T cell signaling, activation, effector differentiation, negative regulation and exhaustion. Nonetheless, the expression of most of these genes was remarkably different between cytokine-primed and antigen-stimulated cells. In addition, cytokine priming impacted the expression of several genes following antigen stimulation in a synergistic or antagonistic manner. Our findings indicate that chromatin accessibility changes in cytokine-primed naive CD8(+) T cells not only underlie their increased antigen responsiveness but may also enhance their functional fitness by reducing exhaustion without compromising regulatory controls.

Automated summary

Cytokine priming enhances antigen responsiveness and functional fitness of naive CD8(+) T cells by modulating chromatin accessibility. This study reveals the molecular mechanisms underlying cytokine priming and its impact on gene expression, suggesting its significance in immune response and regulation.