-
Mehul S Suthar,
Daphne Y Ma,
Sunil Thomas,
Jennifer M Lund,
Nu Zhang,
Stephane Daffis,
Alexander Y Rudensky,
Michael J Bevan,
Edward A Clark, Murali-Krishna Kaja,
Michael S Diamond,
Michael Gale
[show abstract]
[hide abstract]
ABSTRACT: The innate immune response is essential for controlling West Nile virus (WNV) infection but how this response is propagated and regulates adaptive immunity in vivo are not defined. Herein, we show that IPS-1, the central adaptor protein to RIG-I-like receptor (RLR) signaling, is essential for triggering of innate immunity and for effective development and regulation of adaptive immunity against pathogenic WNV. IPS-1(-/-) mice exhibited increased susceptibility to WNV infection marked by enhanced viral replication and dissemination with early viral entry into the CNS. Infection of cultured bone-marrow (BM) derived dendritic cells (DCs), macrophages (Macs), and primary cortical neurons showed that the IPS-1-dependent RLR signaling was essential for triggering IFN defenses and controlling virus replication in these key target cells of infection. Intriguingly, infected IPS-1(-/-) mice displayed uncontrolled inflammation that included elevated systemic type I IFN, proinflammatory cytokine and chemokine responses, increased numbers of inflammatory DCs, enhanced humoral responses marked by complete loss of virus neutralization activity, and increased numbers of virus-specific CD8+ T cells and non-specific immune cell proliferation in the periphery and in the CNS. This uncontrolled inflammatory response was associated with a lack of regulatory T cell expansion that normally occurs during acute WNV infection. Thus, the enhanced inflammatory response in the absence of IPS-1 was coupled with a failure to protect against WNV infection. Our data define an innate/adaptive immune interface mediated through IPS-1-dependent RLR signaling that regulates the quantity, quality, and balance of the immune response to WNV infection.
PLoS Pathogens 01/2010; 6(2):e1000757. · 9.13 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Use of the progesterone (Pg) birth control depot medroxyprogesterone acetate (DMPA) increases a woman's risk for sexually transmitted infection with HIV or HSV-2 via unknown mechanisms. Plasmacytoid dendritic cells (pDCs) are circulating and tissue-resident sentinels capable of making large quantities of IFN-alpha upon recognizing viruses through TLRs 7 and 9. In this study, we show that Pg inhibits TLR9-induced IFN-alpha production by human and mouse pDCs and that DMPA impairs TLR9- and virus-induced IFN-alpha production by pDCs in mice, providing a potential explanation for how DMPA impairs innate antiviral immunity in women. Pg failed to inhibit the Mda-5 pathway of IFN-alpha induction in dendritic cells, suggesting that Pg regulates select antiviral DC programs. This may occur through selective blockade of IFN regulatory factor-7 activation, a novel steroid action. Thus, through inhibition of TLR-mediated IFN-alpha production by pDCs, Pg may regulate antiviral immunity.
The Journal of Immunology 03/2008; 180(4):2029-33. · 5.79 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Activated in immune responses, T lymphocytes differentiate into effector cells with potent immune function. CD28 is the most prominent costimulatory receptor for T-cell activation. However, absence of CD28 costimulation did not completely impair effector function of CD4 or CD8 T cells. Moreover, increasing number of costimulatory molecules are recently found on antigen-presenting cells to regulate T-cell activation. To understand the molecular mechanisms that determine T-cell function or tolerance, we have collectively examined the roles of positive and negative costimulatory molecules. Antigen-specific naïve CD4 and CD8 T cells, only when activated in the absence of both CD28 and ICOS pathways, were completely impaired in effector function. These tolerant T cells not only were anergic with profound defects in TcR signal transduction but also completely lacked expression of effector-specific transcription factors. T-cell tolerance induction in this system requires the action by negative costimulatory molecules; T-cell proliferation and function was partially restored by inhibiting PD-1, B7-H3 or B7S1. This work demonstrates that T-cell function or tolerance is controlled by costimulatory signals.
The EMBO Journal 07/2006; 25(11):2623-33. · 9.20 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The generation and efficient maintenance of antigen specific memory T cells is essential for long-lasting immunological protection. Antigen specific memory CD8 T cells are known to be maintained via antigen-independent homeostatic proliferation. However, signals that drive memory T cell generation and/or influence the slow turnover of memory T cells are unknown. Recently, IL-15 has received attention for its potential effect on memory CD8 T cells. In this report we examine the role of IL-15 in the generation and maintenance of virus specific memory CD8 T cells using mice deficient in either IL-15 or the IL-15 receptor a chain. Both cytokine and receptor deficient mice mount a robust CD8 T cell response to infection with lymphocytic choriomeningitis virus (LCMV) that is initially only slightly lower than in control mice. Further, virus specific memory CD8 T cells are generated in both IL-15 -/- and IL-15Ralpha -/- mice. However, longitudinal analysis reveals a slow attrition of LCMV specific memory CD8 T cells in the absence of IL-15 signals. Indeed, direct examination of homeostatic proliferation reveals a severe defect in the turnover of antigen specific memory CD8 T cells in the absence of IL-15. Together these results suggest that IL-15 is not essential for the generation of memory CD8 T cells, but is required for homeostatic proliferation to maintain populations of memory cells over long periods of time.
Advances in experimental medicine and biology 02/2002; 512:165-75. · 1.09 Impact Factor
