RESUMO
Tumor-induced myeloid-derived suppressor cells (MDSC) contribute to immune suppression in tumor-bearing individuals and are a major obstacle to effective immunotherapy. Reactive oxygen species (ROS) are one of the mechanisms used by MDSC to suppress T cell activation. Although ROS are toxic to most cells, MDSC survive despite their elevated content and release of ROS. NF erythroid 2-related factor 2 (Nrf2) is a transcription factor that regulates a battery of genes that attenuate oxidative stress. Therefore, we hypothesized that MDSC resistance to ROS may be regulated by Nrf2. To test this hypothesis, we used Nrf2(+/+)and Nrf2(-/-)BALB/c and C57BL/6 mice bearing 4T1 mammary carcinoma and MC38 colon carcinoma, respectively. Nrf2 enhanced MDSC suppressive activity by increasing MDSC production of H2O2, and it increased the quantity of tumor-infiltrating MDSC by reducing their oxidative stress and rate of apoptosis. Nrf2 did not affect circulating levels of MDSC in tumor-bearing mice because the decreased apoptotic rate of tumor-infiltrating MDSC was balanced by a decreased rate of differentiation from bone marrow progenitor cells. These results demonstrate that Nrf2 regulates the generation, survival, and suppressive potency of MDSC, and that a feedback homeostatic mechanism maintains a steady-state level of circulating MDSC in tumor-bearing individuals.
Assuntos
Apoptose/imunologia , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/imunologia , Células Mieloides/citologia , Fator 2 Relacionado a NF-E2/imunologia , Evasão Tumoral/imunologia , Animais , Células da Medula Óssea/citologia , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Sobrevivência Celular/imunologia , Neoplasias do Colo/patologia , Feminino , Peróxido de Hidrogênio/metabolismo , Tolerância Imunológica/imunologia , Neoplasias Mamárias Animais/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Células Mieloides/imunologia , Fator 2 Relacionado a NF-E2/biossíntese , Fator 2 Relacionado a NF-E2/genética , Estresse Oxidativo/genética , Células-Tronco/citologiaRESUMO
Maintenance of Th1 responses and dendritic cell (DC) functions are compromised in HIV-1 infected individuals. To better understand these immune abnormalities, we developed an HIV-1 transgenic (Tg) rat. We report that Tg DCs induce elevated levels of SOCS-1 and secrete decreased IL-12p40 and elevated levels of IL-10 following TLR-4 stimulation by LPS. This leads to further induction of SOCS-1 by IL-10 and decreased IFN-gamma-mediated induction of interferon response factor (IRF)-1 and IL-12Rbeta1 expression in CD4+ T cells and to decreased IL-12-induction of IFN-gamma production by Th1 polarized T cells. We also show that SOCS-1 is elevated in CD4+ T cells from HIV-1 infected progressors, and is correlated with defective induction of IRF-1 following IFN-gamma stimulation, compared with healthy controls and HIV-1 natural viral suppressor (NVS) patients. These results suggest a link between high levels of SOCS-1, defects in innate immunity and adaptive Th1 responses that may be reflected in the loss of Th1 immune competence observed with AIDS patients.