Inflammatory disease and lymphomagenesis caused by deletion of the Myc antagonist Mnt in T cells.
Mnt is a Max-interacting protein that can antagonize the activities of Myc oncoproteins in cultured cells. Mnt null mice die soon after birth, but conditional deletion of Mnt in breast epithelium leads to tumor formation. These and related data suggest that Mnt functions as a tumor suppressor. Here we show that conditional deletion of Mnt in T cells leads to tumor formation but also causes inflammatory disease. Deletion of Mnt caused increased apoptosis of thymic T cells and interfered with T-cell development yet led to spleen, liver, and lymph node enlargement. The proportion of T cells in the spleen and lymph nodes was reduced, and the numbers of cells in non-T-cell immune cell populations were elevated. The disruption of immune homeostasis is linked to a strong skewing toward production of T-helper 1 (Th1) cytokines and enhanced proliferation of activated Mnt-deficient CD4+ T cells. Consistent with Th1 polarization in vivo, extensive intestinal inflammation and liver necrosis developed. Finally, most mice lacking Mnt in T cells ultimately succumbed to T-cell lymphoma. These results strengthen the argument that Mnt functions as a tumor suppressor and reveal a critical and surprising role for Mnt in the regulation of T-cell development and in T-cell-dependent immune homeostasis.
Dezfouli
Shala
S
Shriners Hospital for Children, 3181 SW Sam Jackson Park Road, Portland, OR 97239, USA.
Bakke
Antony
A
Huang
Jie
J
Wynshaw-Boris
Anthony
A
Hurlin
Peter J
PJ
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics* / Q000473:pathology; D007422:Intestines / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D009336:Necrosis; D009929:Organ Size; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology / Q000473:pathology; D013950:Thymus Gland / Q000473:pathology
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C484561:Mnt protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins