Menin Plays a Critical Role in the Regulation of the Antigen-Specific CD8+ T Cell Response upon <i>Listeria</i> Infection

Abstract

Menin, a tumor suppressor protein, is encoded by the MEN1 gene in humans. Certain germinal mutations of MEN1 induce an autosomal-dominant syndrome that is characterized by concurrent parathyroid adenomas and several other tumor types. Although menin is also expressed in hematopoietic lineages, its role in CD8⁺ T cells remains unclear. We generated Menin^flox/flox CD4-Cre (Menin-KO) mice by crossing Menin^flox/flox mice with CD4-Cre transgenic (Tg) mice to determine the role of menin in CD8⁺ T cells. Wild-type (WT) and Menin-KO mice were infected with Listeria monocytogenes expressing OVA to analyze the immune response of Ag-specific CD8⁺ T cells. Menin deficiency resulted in an impaired primary immune response by CD8⁺ T cells. On day 7, there were fewer Menin-KO OVA-specific CD8⁺ T cells compared with WT cells. Next, we adoptively transferred WT and Menin-KO OT-1 Tg CD8⁺ T cells into congenic recipient mice and infected them with L. monocytogenes expressing OVA to determine the CD8⁺ T cell-intrinsic effect. Menin-KO OT-1 Tg CD8⁺ T cells were outcompeted by the WT cells upon infection. Increased expression of Blimp-1 and T-bet, cell cycle inhibitors, and proapoptotic genes was observed in the Menin-KO OT-1 Tg CD8⁺ T cells upon infection. These data suggest that menin inhibits differentiation into terminal effectors and positively controls proliferation and survival of Ag-specific CD8⁺ T cells that are activated upon infection. Collectively, our study uncovered an important role for menin in the immune response of CD8⁺ T cells to infection.