Christine A. Biron

Severe Herpesvirus Infections in an Adolescent without Natural Killer Cells

NATURAL killer cells are a population of T-cell–receptornegative (CD3–) lymphocytes that spontaneously mediate the lysis of sensitive target cells. Natural killer cells are similar morphologically ...

TNF/iNOS-Producing Dendritic Cells Mediate Innate Immune Defense against Bacterial Infection

Dendritic cells (DCs) present microbial antigens to T cells and provide inflammatory signals that modulate T cell differentiation. While the role of DCs in adaptive immunity is well established, their involvement in innate immune defenses is less well defined. We have identified a TNF/iNOS-producing (Tip)-DC subset in spleens of Listeria monocytogenes-infected mice that is absent from CCR2-deficient mice. The absence of Tip-DCs results in profound TNF and iNOS deficiencies and an inability to clear primary bacterial infection. CD8 and CD4 T cell responses to L. monocytogenes antigens are preserved in CCR2-deficient mice, indicating that Tip-DCs are not essential for T cell priming. Tip-DCs, as the predominant source of TNF and iNOS during L. monocytogenes infection, orchestrate and mediate innate immune defense against this intracellular bacterial pathogen.

The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions.

Bruce S. McEwen , Christine A. Biron , Kenneth W. Brunson , Karen Bulloch , William H. Chambers , Firdaus S. Dhabhar , Ronald H. Goldfarb , Richard P. Kitson , Andrew H. Miller , Robert L. Spencer , Jay M. Weiss d a Laboratory of Neuroendocrinology, Rockefeller UniÕersity, 1230 York AÕenue, Box 165, New York, NY 10021, USA b DiÕision of Biology and Medicine, Brown UniÕersity, ProÕidence, RI, USA c Pittsburgh Cancer Institute, UniÕersity of Pittsburgh, School of Medicine, Pittsburgh, PA, USA d Department of Psychiatry and BehaÕioral Sciences, Emory UniÕersity School of Medicine, Atlanta, GA, USA

Interferons α and β as Immune Regulators—A New Look

The author thanks Marc Dalod, Khuong (Ken) Nguyen, and George Yap for helpful discussion of this work.

T-bet Regulates the Terminal Maturation and Homeostasis of NK and Vα14i NKT Cells

Natural killer (NK) and CD1d-restricted Valpha14i natural killer T (NKT) cells play a critical early role in host defense. Here we show that mice with a targeted deletion of T-bet, a T-box transcription factor required for Th1 cell differentiation, have a profound, stem cell-intrinsic defect in their ability to generate mature NK and Valpha14i NKT cells. Both cell types fail to complete normal terminal maturation and are present in decreased numbers in peripheral lymphoid organs of T-bet(-/-) mice. T-bet expression is regulated during NK cell differentiation by NK-activating receptors and cytokines known to control NK development and effector function. Our results identify T-bet as a key factor in the terminal maturation and peripheral homeostasis of NK and Valpha14i NKT cells.

Coordinated and distinct roles for IFN-alpha beta, IL-12, and IL-15 regulation of NK cell responses to viral infection

NK cell cytotoxicity, IFN-γ expression, proliferation, and accumulation are rapidly induced after murine CMV infections. Under these conditions, the responses were shown to be elicited in overlapping populations. Nevertheless, there were distinct signaling molecule requirements for induction of functions within the subsets. IL-12/STAT4 was critical for NK cell IFN-γ expression, whereas IFN-αβ/STAT1 were required for induction of cytotoxicity. The accumulation/survival of proliferating NK cells was STAT4-independent but required IFN-αβ/STAT1 induction of IL-15. Taken together, the results define the coordinated interactions between the cytokines IFN-αβ, IL-12, and IL-15 for activation of protective NK cell responses during viral infections, and emphasize these factors’ nonredundant functions under in vivo physiological conditions.

Interferon α/β and Interleukin 12 Responses to Viral Infections Pathways Regulating Dendritic Cell Cytokine Expression In Vivo

Interferon (IFN)-α/β and interleukin (IL)-12 are cytokines critical in defense against viruses, but their cellular sources and mechanisms of regulation for in vivo expression remain poorly characterized. The studies presented here identified a novel subset of dendritic cells (DCs) as major producers of the cytokines during murine cytomegalovirus (MCMV) but not lymphocytic choriomeningitis virus (LCMV) infections. These DCs differed from those activated by Toxoplasma antigen but were related to plasmacytoid cells, as assessed by their CD8α+Ly6G/C+CD11b− phenotype. Another DC subset (CD8α2Ly6G/C−CD11b+) also contributed to IL-12 production in MCMV-infected immunocompetent mice, modestly. However, it dramatically increased IL-12 expression in the absence of IFN-α/β functions. Conversely, IFN-α/β production was greatly reduced under these conditions. Thus, a cross-regulation of DC subset cytokine responses was defined, whereby secretion of type I IFNs by CD8α+ DCs resulted in responses limiting IL-12 expression by CD11b+ DCs but enhancing overall IFN-α/β production. Taken together, these data indicate that CD8α+Ly6G/C+CD11b− DCs play important roles in limiting viral replication and regulating immune responses, through cytokine production, in some but not all viral infections. They also illustrate the plasticity of cellular sources for innate cytokines in vivo and provide new insights into the roles of IFNs in shaping immune responses to viruses.

Activation and function of natural killer cell responses during viral infections

Although the role of natural killer (NK) cells in defense against certain viral infections has been appreciated for a number of years, characterization of the virus-induced endogenous mechanisms regulating NK cell responses and functions has been limited to interferon (IFN)-alpha/beta-mediated activation of NK cell cytotoxicity. Studies of experimental infections have demonstrated that virus-induced NK cells undergo blastogenesis and can be activated to produce IFN-gamma. Recent work has shown that some, but not all, viral infections induce IL-12, the expression of which results in NK cell IFN-gamma production, and that NK cell IFN-gamma production contributes to an antiviral state. IL-12 expression can be regulated by IFN-alpha/beta, and endogenous IFN-alpha/beta is responsible for the lack of IL-12 during viral infections that fail to elicit detectable production of this factor. Once T cell responses are activated, additional mechanisms are in place to turn off NK cell functions. These studies demonstrate that viral infections elicit unique mechanisms for regulating NK cell responses, and suggest that the host requires tight control of NK cells under these conditions.

NK cells and NKT cells in innate defense against viral infections

NK cells contribute to innate defense during certain viral infections, but the mechanisms for their regulation and delivery of antiviral effects are incompletely understood. A second NK cell population, from within T cell populations--NKT cells--has a unique potential to initiate cellular effector mechanisms, including those delivered by NK cells, provided that the antigen for their restricted TCR is induced during infection. If elicited, particular innate cytokine responses promote activation of NK cell cytotoxicity or IFN-gamma production. These responses can contribute to defense by mediating antiviral and/or immunoregulatory effects. Roles of positive or negative receptors for target cells in protection against viruses are less clear. Exciting new data indicate that, in at least one system, NK cell receptors that positively signal for activation participate in the recruitment of these cells into antiviral defense mechanisms. Other recent evidence suggests that NKT cells may be important for protection during one viral infection and may be artificially activated by delivery of antigen to promote antiviral defense. Taken together, these recent advances in the characterization of the NK and NKT cell responses are filling in the details of the complex and critical events taking place, at the earliest times after challenge, to promote resistance to viruses.

Dendritic Cell Responses to Early Murine Cytomegalovirus Infection Subset Functional Specialization and Differential Regulation by Interferon α/β

Differentiation of dendritic cells (DCs) into particular subsets may act to shape innate and adaptive immune responses, but little is known about how this occurs during infections. Plasmacytoid dendritic cells (PDCs) are major producers of interferon (IFN)-α/β in response to many viruses. Here, the functions of these and other splenic DC subsets are further analyzed after in vivo infection with murine cytomegalovirus (MCMV). Viral challenge induced PDC maturation, their production of high levels of innate cytokines, and their ability to activate natural killer (NK) cells. The conditions also licensed PDCs to efficiently activate CD8 T cells in vitro. Non-plasmacytoid DCs induced T lymphocyte activation in vitro. As MCMV preferentially infected CD8α+ DCs, however, restricted access to antigens may limit plasmacytoid and CD11b+ DC contribution to CD8 T cell activation. IFN-α/β regulated multiple DC responses, limiting viral replication in all DC and IL-12 production especially in the CD11b+ subset but promoting PDC accumulation and CD8α+ DC maturation. Thus, during defense against a viral infection, PDCs appear specialized for initiation of innate, and as a result of their production of IFN-α/β, regulate other DCs for induction of adaptive immunity. Therefore, they may orchestrate the DC subsets to shape endogenous immune responses to viruses.