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

Naïve 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, naïve 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 naïve CD8(+) T cells not only underlie their increased antigen responsiveness but may also enhance their functional fitness by reducing exhaustion without compromising regulatory controls.