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Natural killer (NK) cells provide important host defense against herpesvirus infections and influence subsequent T cell control of replication and maintenance of latency. NK cells exhibit phases of expansion, contraction and memory formation in response to the natural mouse pathogen murine cytomegalovirus (MCMV). Innate and adaptive immune responses are tightly regulated in mammals to avoid excess tissue damage while preventing acute and chronic viral disease and assuring resistance to reinfection. Caspase (CASP)8 is an autoactivating aspartate-specific cysteine protease that initiates extrinsic apoptosis and prevents receptor interacting protein (RIP) kinase (RIPK)1-RIPK3-driven necroptosis. CASP8 also promotes death-independent signal transduction. All of these activities make contributions to inflammation. Here, we demonstrate that CASP8 restricts NK cell expansion during MCMV infection but does not influence NK memory. Casp8-/-Ripk3-/- mice mount higher NK response levels than Casp8+/-Ripk3-/- littermate controls or WT C57BL/6 J mice, indicating that RIPK3 deficiency alone does not contribute to NK response patterns. MCMV m157-responsive Ly49H+ NK cells support increased expansion of both Ly49H- NK cells and CD8 T cells in Casp8-/-Ripk3-/- mice. Surprisingly, hyperaccumulation of NK cells depends on the pronecrotic kinase RIPK1. Ripk1-/-Casp8-/-Ripk3-/- mice fail to show the enhanced expansion of lymphocytes observed in Casp8-/-Ripk3-/- mice even though development and homeostasis are preserved in uninfected Ripk1-/-Casp8-/-Ripk3-/- mice. Thus, CASP8 naturally regulates the magnitude of NK cell responses in response to infection where strong activation signals depend on another key regulator of death signaling, RIPK1. In addition, the strong NK cell response promotes survival of effector CD8 T cells during their expansion. Thus, hyperaccumulation of NK cells and crosstalk with T cells becomes amplified in the absence of extrinsic cell death machinery.

Objective: Multidrug-resistant tuberculosis (MDR-TB) causes persistent infection and challenges tuberculosis control worldwide. T cell-mediated immunity plays a critical role in controlling Mycobacterium tuberculosis (Mtb) infection, and therefore, enhancing Mtb-specific T cell immune responses represents a promising therapeutic strategy against TB. Cytokine-induced killer (CIK) immunotherapy is based on autologous infusion of in vitro expanded bulk T cells, which include both pathogen-specific and nonspecific T cells from patient peripheral blood mononuclear cells (PBMC) into TB patients. Preclinical mouse studies have shown that the adoptive T cell therapy inhibited Mtb infection. However, the efficacy of CIK immunotherapy in the treatment of MDR-TB infection has not been evaluated in clinical trials.Methods: We performed a retrospective study of MDR-TB patients who received CIK immunotherapy in combination with anti-TB chemotherapy and those who had standard chemotherapy.Results: Our results showed that CIK immunotherapy in combination with anti-TB chemotherapy treatment increased the conversion rate of sputum smear and Mtb culture, alleviated symptoms, improved lesion absorption, and increased recovery. The kinetics of serology and immunology index monitoring data showed good safety profiles for the CIK treatment.Conclusion: Our study has provided strong evidence that CIK immunotherapy in combination with anti-TB chemotherapy is beneficial for MDR-TB patients. A multicenter clinical trial is warranted to evaluate CIK as a new immune therapy for MDR-TB. [ABSTRACT FROM AUTHOR]

Z‐nucleic acid binding protein (ZBP)1 (also known as DAI and DLM1) is a pathogen sensor activated by double‐strand character RNA to recruit receptor‐interacting protein (RIP) kinase via a RIP homotypic interaction motif. The activation of receptor‐interacting protein kinase (RIPK)3 and initiation of virus‐induced necroptosis were initially reported in a landmark publication Upton et al. (Cell Host Microbe11: 290, 2012) employing the DNA virus murine cytomegalovirus (MCMV). M45‐encoded viral inhibitor of RIP activation prevents virus‐induced necroptosis. Additional virus‐encoded suppressors of necroptosis were then identified, including herpes simplex virus ICP6 and vaccinia virus E3L. Caspase‐8 suppressors encoded by these DNA viruses block apoptosis, unleashing necroptosis mediated through Z‐nucleic acid binding protein 1 (ZBP1) recruitment of RIPK3. These studies all utilized ZBP1‐deficient mice generated by the Akira Lab (Zbp1−/− AK) to bring the significance of virus‐induced necroptosis to light. C57BL/6 mice were chosen as controls based on the assumption that mutant mice were congenic; however, these mice were recently found to display an unexpected innate immune deficit, lacking C57BL/6‐specific NK1.1 and Ly49H natural killer cell subpopulations important in the early control of MCMV infection. Short nucleotide polymorphism analysis of Zbp1−/− AK breeders revealed a mixed genetic background (~ 71% C57BL/6 DNA and ~ 29% 129). Even though this level of 129 strain background does not alter ZBP1 cell‐autonomous function as a sensor and mediator of necroptosis, it confounds innate immune response characteristics. In the future, genetic background must be carefully controlled before implicating ZBP1 function in response characteristics that shape immunity, inflammation, metabolism, and pathogenesis. [ABSTRACT FROM AUTHOR]

Caspase-8 (CASP8) impacts antiviral immunity in expected as well as unexpected ways. Mice with combined deficiency in CASP8 and RIPK3 cannot support extrinsic apoptosis or RIPK3-dependent programmed necrosis, enabling studies of CASP8 function without complications of unleashed necroptosis. These extrinsic cell death pathways are naturally targeted by murine cytomegalovirus (MCMV)-encoded cell death suppressors, showing they are key to cell-autonomous host defense. Remarkably, Casp8–/–Ripk3–/–, Ripk1–/–Casp8–/–Ripk3–/– and Casp8–/–Ripk3K51A/K51A mice mount robust antiviral T cell responses to control MCMV infection. Studies in Casp8–/–Ripk3–/– mice show that CASP8 restrains expansion of MCMV-specific natural killer (NK) and CD8 T cells without compromising contraction or immune memory. Infected Casp8–/–Ripk3–/– or Casp8–/–Ripk3K51A/K51A mice have higher levels of virus-specific NK cells and CD8 T cells compared to matched RIPK3-deficient littermates or WT mice. CASP8, likely acting downstream of Fas death receptor, dampens proliferation of CD8 T cells during expansion. Importantly, contraction proceeds unimpaired in the absence of extrinsic death pathways owing to intact Bim-dependent (intrinsic) apoptosis. CD8 T cell memory develops in Casp8–/–Ripk3–/– mice, but memory inflation characteristic of MCMV infection is not sustained in the absence of CASP8 function. Despite this, Casp8–/–Ripk3–/– mice are immune to secondary challenge. Interferon (IFN)γ is recognized as a key cytokine for adaptive immune control of MCMV. Ifngr–/–Casp8–/–Ripk3–/– mice exhibit increased lifelong persistence in salivary glands as well as lungs compared to Ifngr–/– and Casp8–/–Ripk3–/– mice. Thus, mice deficient in CASP8 and RIPK3 are more dependent on IFNγ mechanisms for sustained T cell immune control of MCMV. Overall, appropriate NK- and T cell immunity to MCMV is dependent on host CASP8 function independent of RIPK3-regulated pathways. [ABSTRACT FROM AUTHOR]