Tuberculosis remains second only to HIV/AIDS as the leading cause of mortality worldwide due to a single infectious agent1. Despite chemotherapy, the global tuberculosis epidemic has intensified because of HIV co-infection, the lack of an effective vaccine and the emergence of multi-drug-resistant bacteria2–5. Alternative host-directed strategies could be exploited to improve treatment efficacy and outcome, contain drug-resistant strains and reduce disease severity and mortality6. The innate inflammatory response elicited by Mycobacterium tuberculosis (Mtb) represents a logical host target7. Here we demonstrate that interleukin-1 (IL-1) confers host resistance through the induction of eicosanoids that limit excessive type I interferon (IFN) production and foster bacterial containment. We further show that, in infected mice and patients, reduced IL-1 responses and/or excessive type I IFN induction are linked to an eicosanoid imbalance associated with disease exacerbation. Host-directed immunotherapy with clinically approved drugs that augment prostaglandin E2 levels in these settings prevented acute mortality of Mtb-infected mice. Thus, IL-1 and type I IFNs represent two major counter-regulatory classes of inflammatory cytokines that control the outcome of Mtb infection and are functionally linked via eicosanoids. Our findings establish proof of concept for host-directed treatment strategies that manipulate the host eicosanoid network and represent feasible alternatives to conventional chemotherapy.

Administration of daclizumab, a humanized mAb directed against the IL-2R␣ chain, strongly reduces brain inflammation in multiple sclerosis patients. Here we show that daclizumab treatment leads to only a mild functional blockade of CD4 ؉ T cells, the major candidate in multiple sclerosis pathogenesis. Instead, daclizumab therapy was associated with a gradual decline in circulating CD4 ؉ and CD8 ؉ T cells and significant expansion of CD56 bright natural killer (NK) cells in vivo, and this effect correlated highly with the treatment response. In vitro studies showed that NK cells inhibited T cell survival in activated peripheral blood mononuclear cell cultures by a contact-dependent mechanism. Positive correlations between expansion of CD56 bright NK cells and contraction of CD4 ؉ and CD8 ؉ T cell numbers in individual patients in vivo provides supporting evidence for NK cell-mediated negative immunoregulation of activated T cells during daclizumab therapy. Our data support the existence of an immunoregulatory pathway wherein activated CD56 bright NK cells inhibit T cell survival. This immunoregulation has potential importance for the treatment of autoimmune diseases and transplant rejection and toward modification of tumor immunity.CD25 ͉ IL-2 ͉ immunoregulatory natural killer cells M ultiple sclerosis (MS) is an inflammatory͞demyelinating disease of the CNS that is one of the leading causes of neurological disability in young adults (1). It is believed that MS is a T cell-mediated autoimmune disease, and therefore the search for new therapies focuses on agents that affect lymphocyte function. Daclizumab (Zenapax), a humanized mAb that blocks the IL-2 binding site on the IL-2R␣ chain, CD25 (i.e., Tac epitope), is among these novel agents (2). The IL-2R complex is comprised of three subunits: IL-2R␣ (CD25), IL-2R␤ (CD122), and IL-2R␥ (CD132). CD122 and CD132 have intracellular signaling motifs and together form the intermediate-affinity (K dis Ϸ 0.1-1 nM) IL-2R. CD25 binds IL-2 with low (K dis Ϸ 10 nM) affinity, but when it associates with CD122͞CD132 it stabilizes the complex to form the highaffinity (K dis Ϸ 10 pM) receptor (3). CD25 is present at low levels in resting human T cells (with the exception of T regulatory cells) but is significantly up-regulated on activated T cells, enabling them to receive a high-affinity IL-2 signal (4). Therefore, it is believed that the blockade of CD25 will result in selective functional inhibition of activated T cells (5). Although it has been demonstrated that daclizumab (or the original murine anti-Tac mAb) inhibits early IL-2R signal transduction events (6, 7) and blocks T cell activation and expansion in vitro (8), a comprehensive characterization of its in vivo effects is still lacking.We recently concluded a phase II, open-label, baseline-versustreatment crossover trial of daclizumab in 10 MS patients with incomplete therapeutic response to IFN-␤. Daclizumab showed a profound inhibitory effect on brain inflammatory activity (78% reduction) and subsequent stabilization o...

Generation of CD8