Significance Rapamycin is an immunosuppressive drug that partially inhibits the cellular kinase mammalian target of rapamycin (mTOR). This study uncovers previously unidentified mechanisms of mTOR signaling in B cells. Antigen recognition and other signals activate mTOR, a central driver of lymphocyte proliferation and differentiation. However, mTOR forms two protein complexes (mTORC1 and mTORC2) whose roles in B-cell differentiation are poorly defined. We found that a new class of ATP-competitive mTOR kinase inhibitors (TOR-KIs) can augment antibody class switching at concentrations that partially inhibit mTOR activity. Mechanistic studies indicate that mTORC1 loss suppresses, whereas mTORC2 loss promotes, class switching. The dominant effect of TOR-KIs is to promote switching through mTORC2 inhibition. These findings establish distinct immunomodulatory activity of TOR-KIs compared with the canonical mTOR inhibitor rapamycin.