Martha Jordan

"TET2 controls differentiation of terminally exhausted CD8 T cells"

Amy E. Baxter, Sydney Drury, Josephine R. Giles, Sasikanth Manne, Hua Huang, Zeyu Chen, Derek Oldridge, E. John Wherry and Martha S. Jordan

CD8 T cells are critical for clearing infections and immune surveillance of cancers. However, in the setting of chronic viral infections and tumor growth, CD8 T cells become exhausted. T cell exhaustion (TEX) is characterized by a progressive increase of inhibitory receptor expression and concomitant diminishment of effector function. This diminished function renders the host unable to clear the virus or cancer. The TEX population is heterogenous and can be divided broadly into TEX progenitor and TEX terminal populations. TEX progenitor are self-renewing, responsive to PD-1 blockade and give rise to the later TEX subsets, including short-lived TEX terminal cells. Control of DNA demethylation is required in multiple settings for maintenance or loss of stem-like characteristics. We report that TET2, a methylcytosine dioxygenase that mediates active DNA demethylation, is required for TEX progenitors to differentiate fully into TEX terminal cells. TET2-deficiency during persistent viral infection resulted in a numerical loss of TEX terminal cells, while maintaining the TEX progenitor population. The TEX terminal cells that escaped this differentiation block retained some features of TEX progenitors, including decreased expression of several inhibitory receptors. TET2- deficient TEX progenitors responded to PD-1 blockade but were unable to establish expansion of TEX cells thought to be required for viral control. These data highlight the role of DNA methylation and TET2 in establishing TEX diversity.