TNF-α-dependent hematopoiesis following Bcl11b deletion in T cells restricts metastatic melanoma.
Using several tumor models, we demonstrate that mice deficient in Bcl11b in T cells, although having reduced numbers of T cells in the peripheral lymphoid organs, developed significantly less tumors compared with wild-type mice. Bcl11b(-/-) CD4(+) T cells, with elevated TNF-α levels, but not the Bcl11b(-/-) CD8(+) T cells, were required for the reduced tumor burden, as were NK1.1(+) cells, found in increased numbers in Bcl11b(F/F)/CD4-Cre mice. Among NK1.1(+) cells, the NK cell population was predominant in number and was the only population displaying elevated granzyme B levels and increased degranulation, although not increased proliferation. Although the number of myeloid-derived suppressor cells was increased in the lungs with metastatic tumors of Bcl11b(F/F)/CD4-Cre mice, their arginase-1 levels were severely reduced. The increase in NK cell and myeloid-derived suppressor cell numbers was associated with increased bone marrow and splenic hematopoiesis. Finally, the reduced tumor burden, increased numbers of NK cells in the lung, and increased hematopoiesis in Bcl11b(F/F)/CD4-Cre mice were all dependent on TNF-α. Moreover, TNF-α treatment of wild-type mice also reduced the tumor burden and increased hematopoiesis and the numbers and activity of NK cells in the lung. In vitro treatment with TNF-α of lineage-negative hematopoietic progenitors increased NK and myeloid differentiation, further supporting a role of TNF-α in promoting hematopoiesis. These studies reveal a novel role for TNF-α in the antitumor immune response, specifically in stimulating hematopoiesis and increasing the numbers and activity of NK cells.
Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208.
Mohammad N
MN
Uddin
Yubin
Y
Zhang
Jonathan A
JA
Harton
Katherine C
KC
MacNamara
Dorina
D
Avram
D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism; D001119:Arginase / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015550:Cell Degranulation / Q000276:immunology; D049109:Cell Proliferation; D017353:Gene Deletion; D053804:Granzymes / Q000378:metabolism; D006410:Hematopoiesis; D007694:Killer Cells, Natural / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology; D018655:Lymphocyte Count; D008545:Melanoma / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D047368:Tumor Burden / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
D000950:Antigens, Ly; C511143:Bcl11b protein, mouse; C527211:Klrb1c protein, mouse; D055651:NK Cell Lectin-Like Receptor Subfamily B; D012097:Repressor Proteins; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D053804:Granzymes; C544448:Arg1 protein, mouse; D001119:Arginase