The Deubiquitinase USP22 Modulates Regulatory T-cell Function

Loss of the master transcription factor FOXP3 is associated with instability of regulatory T (T_reg) cells. Because T_reg activity can suppress antitumor immune responses, knowledge of the mechanisms by which FOXP3 activity is regulated could yield novel anticancer therapies. Cortez, Montauti, and colleagues performed a CRISPR–Cas9-based screen in mouse T_reg cells and discovered previously unknown regulators of FOXP3, including members of the chromatin-modifying transcriptional coactivator complex SAGA. In particular, the deubiquitinase USP22 was highlighted as a positive regulator of FOXP3. Consistent with this screen result, mouse T_reg cells lacking USP22 had lower levels of FOXP3 and exhibited reduced ability to suppress effector T cells. Mechanistically, USP22 appeared to affect FOXP3 expression at both the transcriptional and posttranscriptional level by causing histone deubiquitination across the Foxp3 locus (leading to increased Foxp3 transcription) and FOXP3 deubiquitination (leading to increased FOXP3 stability), respectively, in mouse T_reg cells. Additionally, the E3 ubiquitin ligase RNF20—which was also identified as a regulator of FOXP3 in the screen—opposed the effects of USP22 on FOXP3 in these cells. Experiments assessing the autoimmune disease–like effects of Usp22 knockout in T cells indicated a specific role for USP22 in regulating FOXP3-mediated T_reg-cell function rather than a general role in all T-cell types. Finally, improved antitumor immunity was observed in a mouse model of T-cell lymphoma in T_reg cell–specific Usp22-knockout mice, likely owing to an observed increased response by cytotoxic CD8⁺ T cells enabled by a decrease in T_reg cell–imposed suppression. Together, these results demonstrate a key role for USP22 in antitumor immunity and suggest that this deubiquitinase may be a promising target for immunotherapy.

Cortez JT, Montauti E, Shifrut E, Gatchalian J, Zhang Y, Shaked O, et al. CRISPR screen in regulatory T cells reveals modulators of Foxp3. Nature 2020 Apr 29 [Epub ahead of print].

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