c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells

The transcription factor c-Maf induces the anti-inflammatory cytokine IL-10 in CD4+ T cells in vitro. However, the global effects of c-Maf on diverse immune responses in vivo are unknown. Here we found that c-Maf regulated IL-10 production in CD4+ T cells in disease models involving the TH1 subset of helper T cells (malaria), TH2 cells (allergy) and TH17 cells (autoimmunity) in vivo. Although mice with c-Maf deficiency targeted to T cells showed greater pathology in TH1 and TH2 responses, TH17 cell–mediated pathology was reduced in this context, with an accompanying decrease in TH17 cells and increase in Foxp3+ regulatory T cells. Bivariate genomic footprinting elucidated the c-Maf transcription-factor network, including enhanced activity of NFAT; this led to the identification and validation of c-Maf as a negative regulator of IL-2. The decreased expression of the gene encoding the transcription factor RORγt (Rorc) that resulted from c-Maf deficiency was dependent on IL-2, which explained the in vivo observations. Thus, c-Maf is a positive and negative regulator of the expression of cytokine-encoding genes, with context-specific effects that allow each immune response to occur in a controlled yet effective manner

c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4(+) T cells

The transcription factor c-Maf induces the anti-inflammatory cytokine IL-10 in CD4(+) T cells in vitro. However, the global effects of c-Maf on diverse immune responses in vivo are unknown. Here we found that c-Maf regulated IL-10 production in CD4(+) T cells in disease models involving the T(H)1 subset of helper T cells (malaria), T(H)2 cells (allergy) and T(H)17 cells (autoimmunity) in vivo. Although mice with c-Maf deficiency targeted to T cells showed greater pathology in T(H)1 and T(H)2 responses, T(H)17 cell-mediated pathology was reduced in this context, with an accompanying decrease in T(H)17 cells and increase in Foxp3(+) regulatory T cells. Bivariate genomic footprinting elucidated the c-Maf transcription-factor network, including enhanced activity of NFAT; this led to the identification and validation of c-Maf as a negative regulator of IL-2. The decreased expression of the gene encoding the transcription factor ROR?t (Rorc) that resulted from c-Maf deficiency was dependent on IL-2, which explained the in vivo observations. Thus, c-Maf is a positive and negative regulator of the expression of cytokine-encoding genes, with context-specific effects that allow each immune response to occur in a controlled yet effective manner

MEK inhibitors selectively suppress alloreactivity and graft-versus-host disease in a memory stage-dependent manner

Immunosuppressive strategies currently used in hematopoietic stem cell transplantation reliably decrease graft-versus-host disease (GVHD) rates, but also impair pathogen-specific immunity. Experimental transplant studies indicate that GVHD-initiating alloreactive T cells reside primarily in naive and central memory T-cell compartments. In contrast, virus-specific T cells comprise a more differentiated memory population. After finding that the rat sarcoma/mitogen-activated protein kinase kinase/extracellular receptor kinase (RAS/MEK/ERK) pathway is preferentially activated in naive and central memory human T cells, we hypothesized that MEK inhibitors would preferentially inhibit alloreactive T cells, while sparing more differentiated virus-specific T cells. Confirming our hypothesis, we found that MEK inhibitors including selumetinib preferentially inhibited cytokine production and alloreactivity mediated by naive and central memory human CD4(+) and CD8(+) T cells while sparing more differentiated T cells specific for the human herpesviruses cytomegalovirus and Epstein-Barr virus. We then demonstrated that short-term posttransplant administration of selumetinib in a major histocompatibility complex major- and minor-mismatched murine model significantly delayed the onset of GVHD-associated mortality without compromising myeloid engraftment, demonstrating the in vivo potential of MEK inhibitors in the setting of hematopoietic stem cell transplantation. These findings demonstrate that targeting memory-dependent differences in T-cell signaling is a potent and selective approach to inhibition of alloreactivity

Bacterial Manipulation of NK Cell Regulatory Activity Increases Susceptibility to <i>Listeria monocytogenes</i> Infection

<div><p>Natural killer (NK) cells produce interferon (IFN)-γ and thus have been suggested to promote type I immunity during bacterial infections. Yet, <i>Listeria monocytogenes</i> (Lm) and some other pathogens encode proteins that cause increased NK cell activation. Here, we show that stimulation of NK cell activation increases susceptibility during Lm infection despite and independent from robust NK cell production of IFNγ. The increased susceptibility correlated with IL-10 production by responding NK cells. NK cells produced IL-10 as their IFNγ production waned and the Lm virulence protein p60 promoted induction of IL-10 production by mouse and human NK cells. NK cells consequently exerted regulatory effects to suppress accumulation and activation of inflammatory myeloid cells. Our results reveal new dimensions of the role played by NK cells during Lm infection and demonstrate the ability of this bacterial pathogen to exploit the induction of regulatory NK cell activity to increase host susceptibility.</p></div