Inflammatory signals are sufficient to elicit TOX expression in mouse and human CD8 T cells

Abstract

T cell receptor (TCR) stimulation leads to expression of the transcription factor TOX. Prolonged TCR signaling, such as encountered during chronic infections or in tumors, leads to sustained TOX expression, which induces a state of exhaustion or dysfunction. While CD8 memory T cells (Tmem) in specific pathogen-free laboratory mice typically do not express TOX, functional human Tmem show heterogeneous TOX expression levels. Whether TCR-independent mechanisms can alter TOX expression in human and murine Tmem has not been defined. We report that human and mouse Tmem increase TOX expression following stimulation with inflammatory cytokines IL-12, IL-15, and IL-18. TOX and PD-1 expression patterns often appear to be directly correlated, however, we found that TOX is not necessary for cytokine-driven expression of PD-1. Together, these observations highlight that inflammation is sufficient to alter TOX and PD-1 expression and that the signals regulating TOX expression appear well conserved in human and murine Tmem.

Altered costimulatory signals and hypoxia support chromatin landscapes limiting the functional potential of exhausted T cells in cancer

“…To determine the relationship of Tox binding to the epigenetic changes identified above, we performed CUT&RUN for Tox in our TIL subsets. Although Tox increases in expression as cells progress towards terminal exhaustion, Tox is expressed at low levels in progenitor cells( 11, 12, 28-30 ). Therefore, we were able to identify DEP of Tox in both progenitor and terminally exhausted CD8 T cells (Fig 4A).…”