CRISPR screens unveil signal hubs for nutrient licensing of T cell immunity

Lingyun Long, Jun Wei, Seon Ah Lim, Jana L. Raynor, Hao Shi, Jon P. Connelly, Hong Wang, Cliff Guy, Boer Xie, Nicole M. Chapman, Guotong Fu, Yanyan Wang, Hongling Huang, Wei Su, Jordy Saravia, Isabel Risch, Yong-Dong Wang, Yuxin Li, Mingming Niu, Yogesh Dhungana, Anil Kc, Peipei Zhou, Peter Vogel, Jiyang Yu, Shondra M. Pruett-Miller, Junmin Peng and Hongbo Chi ()
Additional contact information
Lingyun Long: St. Jude Children’s Research Hospital
Jun Wei: St. Jude Children’s Research Hospital
Seon Ah Lim: St. Jude Children’s Research Hospital
Jana L. Raynor: St. Jude Children’s Research Hospital
Hao Shi: St. Jude Children’s Research Hospital
Jon P. Connelly: St. Jude Children’s Research Hospital
Hong Wang: St. Jude Children’s Research Hospital
Cliff Guy: St. Jude Children’s Research Hospital
Boer Xie: St. Jude Children’s Research Hospital
Nicole M. Chapman: St. Jude Children’s Research Hospital
Guotong Fu: St. Jude Children’s Research Hospital
Yanyan Wang: St. Jude Children’s Research Hospital
Hongling Huang: St. Jude Children’s Research Hospital
Wei Su: St. Jude Children’s Research Hospital
Jordy Saravia: St. Jude Children’s Research Hospital
Isabel Risch: St. Jude Children’s Research Hospital
Yong-Dong Wang: St. Jude Children’s Research Hospital
Yuxin Li: St. Jude Children’s Research Hospital
Mingming Niu: St. Jude Children’s Research Hospital
Yogesh Dhungana: St. Jude Children’s Research Hospital
Anil Kc: St. Jude Children’s Research Hospital
Peipei Zhou: St. Jude Children’s Research Hospital
Peter Vogel: St. Jude Children’s Research Hospital
Jiyang Yu: St. Jude Children’s Research Hospital
Shondra M. Pruett-Miller: St. Jude Children’s Research Hospital
Junmin Peng: St. Jude Children’s Research Hospital
Hongbo Chi: St. Jude Children’s Research Hospital

Nature, 2021, vol. 600, issue 7888, 308-313

Abstract: Abstract Nutrients are emerging regulators of adaptive immunity1. Selective nutrients interplay with immunological signals to activate mechanistic target of rapamycin complex 1 (mTORC1), a key driver of cell metabolism2–4, but how these environmental signals are integrated for immune regulation remains unclear. Here we use genome-wide CRISPR screening combined with protein–protein interaction networks to identify regulatory modules that mediate immune receptor- and nutrient-dependent signalling to mTORC1 in mouse regulatory T (Treg) cells. SEC31A is identified to promote mTORC1 activation by interacting with the GATOR2 component SEC13 to protect it from SKP1-dependent proteasomal degradation. Accordingly, loss of SEC31A impairs T cell priming and Treg suppressive function in mice. In addition, the SWI/SNF complex restricts expression of the amino acid sensor CASTOR1, thereby enhancing mTORC1 activation. Moreover, we reveal that the CCDC101-associated SAGA complex is a potent inhibitor of mTORC1, which limits the expression of glucose and amino acid transporters and maintains T cell quiescence in vivo. Specific deletion of Ccdc101 in mouse Treg cells results in uncontrolled inflammation but improved antitumour immunity. Collectively, our results establish epigenetic and post-translational mechanisms that underpin how nutrient transporters, sensors and transducers interplay with immune signals for three-tiered regulation of mTORC1 activity and identify their pivotal roles in licensing T cell immunity and immune tolerance.

Date: 2021
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DOI: 10.1038/s41586-021-04109-7

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