Innate Immunity to Viruses: Control of Vaccinia Virus Infection by    T Cells (original) (raw)

Innate Immunity to Viruses: Control of Vaccinia Virus Infection by γδ T Cells

The Journal of Immunology, 2001

The existence of γδ T cells has been known for over 15 years, but their significance in innate immunity to virus infections has not been determined. We show here that γδ T cells are well suited to provide a rapid response to virus infection and demonstrate their role in innate resistance to vaccinia virus (VV) infection in both normal C57BL/6 and β TCR knockout (KO) mice. VV-infected mice deficient in γδ T cells had significantly higher VV titers early postinfection (PI) and increased mortality when compared with control mice. There was a rapid and profound VV-induced increase in IFN-γ-producing γδ T cells in the peritoneal cavity and spleen of VV-infected mice beginning as early as day 2 PI. This rapid response occurred in the absence of priming, as there was constitutively a significant frequency of VV-specific γδ T cells in the spleen in uninfected β TCR KO mice, as demonstrated by limiting dilution assay. Also, like NK cells, another mediator of innate immunity to viruses, γδ T ...

Innate immunity to viruses: control of vaccinia virus infection by gamma delta T cells

The Journal of Immunology, 2001

The existence of gammadelta T cells has been known for over 15 years, but their significance in innate immunity to virus infections has not been determined. We show here that gammadelta T cells are well suited to provide a rapid response to virus infection and demonstrate their role in innate resistance to vaccinia virus (VV) infection in both normal C57BL/6 and beta TCR knockout (KO) mice. VV-infected mice deficient in gammadelta T cells had significantly higher VV titers early postinfection (PI) and increased mortality when compared with control mice. There was a rapid and profound VV-induced increase in IFN-gamma-producing gammadelta T cells in the peritoneal cavity and spleen of VV-infected mice beginning as early as day 2 PI. This rapid response occurred in the absence of priming, as there was constitutively a significant frequency of VV-specific gammadelta T cells in the spleen in uninfected beta TCR KO mice, as demonstrated by limiting dilution assay. Also, like NK cells, another mediator of innate immunity to viruses, gammadelta T cells in uninfected beta TCR KO mice expressed constitutive cytolytic activity. This cytotoxicity was enhanced and included a broader range of targets after VV infection. VV-infected beta TCR KO mice cleared most of the virus by day 8 PI, the peak of the gammadelta T cell response, but thereafter the gammadelta T cell number declined and the virus recrudesced. Thus, gammadelta T cells can be mediators of innate immunity to viruses, having a significant impact on virus replication early in infection in the presence or absence of the adaptive immune response.

Review paper Innate and adaptive immunity in viral infections

Central European Journal of Immunology, 2011

The defense against viruses requires collaboration of both arms of immunity, innate and adaptive one. Factors of the former may sense viruses early on the principle self/non self and mount fast reaction of the host. Early recognition of intracellular viral invasion is mainly done by pattern recognition receptors (PRRs). It results in the induction of complex inflammatory process composed of proinflammatory agents, collectively named inflammasome. Its formation has a pivotal role in the formation of adaptive response. Infected cells may be also eliminated by natural killer (NK) cells, able to recognize such cells as non-self. Adaptive immunity, both humoral and cellular, is formed later than innate one. Antibodies have a neutralizing effect on viruses, while they are still outside target cells. Cytotoxic T lymphocytes (CTLs) may recognize infected cells and kill them by apoptosis. They are, however, usually too few, to totally eliminate viral infection. Resistance to the progression of HIV/AIDS infection in some individuals is due to the presence of particular HLA alleles, which influence the induction of CTLs directed versus dominant epitope (p24 Gag) of virus. Besides, most viruses possess various escape mechanisms from immune response. Thus, efficient battle with viral infections still remains a formidable challenge.

Cellular and Humoral Immunity against Vaccinia Virus Infection of Mice

The Journal of Immunology, 2004

Despite the widespread use of vaccinia virus (VV) as a vector for other Ags and as the smallpox vaccine, there is little information available about the protective components of the immune response following VV infection. In this study, protection against wild-type VV was evaluated in mice with respect to the relative contributions of CD8 ؉ T cells vs that of CD4 ؉ T cells and Ab. C57BL/6 mice primed with the Western Reserve strain of VV mount significant IgM and IgG Ab responses, specific cytotoxic T cell responses, IFN-␥ responses in CD4 ؉ and CD8 ؉ T cells, and effectively clear the virus. This protection was abrogated by in vivo depletion of CD4 ؉ T cells or B cells in IgH ؊/؊ mice, but was not sensitive to CD8 ؉ T cell depletion alone. However, a role for CD8 ؉ T cells in primary protection was demonstrated in MHC class II ؊/؊ mice, where depleting CD8 ؉ T cells lead to increase severity of disease. Unlike control MHC class II ؊/؊ mice, the group depleted of CD8 ؉ T cells developed skin lesions on the tail and feet and had adrenal necrosis. Adoptive transfer experiments also show CD8 ؉ T cells can mediate protective memory. These results collectively show that both CD4 ؉ and CD8 ؉ T cell-mediated immunity can contribute to protection against VV infection. However, CD4 ؉ T cell-dependent anti-virus Ab production plays a more important role in clearing virus following acute infection, while in the absence of Ab, CD8 ؉ T cells can contribute to protection against disease.

Vaccinia Virus Inhibits T Cell Receptor–Dependent Responses by Human γδ T Cells

The Journal of Infectious Diseases, 2007

Vaccinia virus (VV), a member of the poxvirus family, has been used successfully as a vaccine to eradicate human smallpox [1]. With DNA replication occurring exclusively in the cytosol and the ability to induce both cellular and humoral immunity, VV has also been championed as a live recombinant vaccine vector that promotes immunity against tumors and infectious diseases . Although VV can induce strong humoral and cellular immune responses to viral and recombinant antigens, it is also known that poxviruses employ many mechanisms to evade host immunity. VV gene products block complement, cytokines, and chemokines; they also prevent apoptosis and interfere with intracellular signaling . VV modulates the function of NK cells , inhibits the maturation of human dendritic cells , and disrupts major histocompatibility complex (MHC) class I or II-mediated antigen presentation . The effects that VV has on another important cell type, gd T cells, is poorly understood.

T Cells in Viral Infections: The Myriad Flavours of Antiviral Immunity

Dynamics of Immune Activation in Viral Diseases, 2020

Viral diseases are a major cause of morbidity and mortality and result in a significant public health burden. T lymphocytes first identified in the chordate lineage and constitute a highly sophisticated branch of adaptive immune system. Apart from B cells, it is the only cell type that exhibits antigenic specificities; achieved by gene rearrangement. T cells are unique with respect to diversity of their subsets, which have distinct effector specificities, proliferative abilities, memory generation, and life span. T cells are impactful in viral infections by virtue of their capability to combat intracellular pathogens. The effector functions of T cells are mediated through cytokines/chemokines and by direct cytotoxicity of infected cells. T cell response can be beneficial or detrimental to host; prognosis depending on qualitative and quantitative differences in the response. Persistent viral infections are associated with functionally suboptimal, exhausted T cell responses, which are unable to clear virus. Specific subsets such as regulatory T cells (Tregs) dampen antiviral responses; thereby favouring viral persistence. However, Tregs protect the host from immunopathology by limiting perpetual inflammation. Certain other subsets such as Th17 cells may contribute to autoimmune component of viral infections. The importance of T cells is highlighted by the fact that modern vaccination and therapeutic approaches focus on modulating T cell frequencies and effector functions. This chapter emphasises the understanding how T cells influence outcomes of viral infections, modern vaccination and therapeutic strategies with thrust on T cell biology.

T-bet Is Required for Protection against Vaccinia Virus Infection

Journal of Virology, 2005

The transcription factor T-bet regulates the differentiation of CD4 ؉ T-helper type 1 (Th1) cells and represses Th2 lineage commitment. Since Th1 cells are crucial in the defense against pathogens, several studies addressed the role of T-bet in immunity to infection using T-bet knockout (T-bet ؊/؊ ) mice. Nevertheless, it is still unclear whether T-bet is required for defense. Although vaccinia virus (VV) has extensively been used as an expression vector and the smallpox vaccine, there is only limited knowledge about immunity to VV infection. The urgency to understand the immune responses has been increased because of concerns about bioterrorism. Here, we show that T-bet is critical in the defense against VV infection as follows: (i) the survival rate of T-bet ؊/؊ mice was lower than that of control littermates postinfection; (ii) T-bet ؊/؊ mice lost more weight postinfection; and (iii) control mice cleared VV faster than T-bet ؊/؊ mice. As expected, a significant Th2 shift was observed in CD4 ؉ T cells of T-bet ؊/؊ mice. Furthermore, absence of T-bet impaired VV-specific CD8 ؉ cytotoxic T-lymphocyte (CTL) function, including cytolytic activity, antiviral cytokine production, and proliferation. Cytolytic capacity of natural killer (NK) cells was also diminished in T-bet ؊/؊ mice, whereas anti-VV antibody production was not impaired. These data reveal that the enhanced susceptibility to VV infection in T-bet ؊/؊ mice was at least partially due to the Th2 shift of CD4 ؉ T cells and the diminished function of VV-specific CTLs and NK cells but not due to downregulation of antibody production.

Distinct Requirements for Activation of NKT and NK Cells during Viral Infection

The Journal of Immunology, 2014

NK cells are key regulators of innate defense against mouse CMV (MCMV). Like NK cells, NKT cells also produce high levels of IFN-g rapidly after MCMV infection. However, whether similar mechanisms govern activation of these two cell types, as well as the significance of NKT cells for host resistance, remain unknown. In this article, we show that, although both NKT and NK cells are activated via cytokines, their particular cytokine requirements differ significantly in vitro and in vivo. IL-12 is required for NKT cell activation in vitro but is not sufficient, whereas NK cells have the capacity to be activated more promiscuously in response to individual cytokines from innate cells. In line with these results, GM-CSF-derived dendritic cells activated only NK cells upon MCMV infection, consistent with their virtual lack of IL-12 production, whereas Flt3 ligand-derived dendritic cells produced IL-12 and activated both NK and NKT cells. In vivo, NKT cell activation was abolished in IL-12 2/2 mice infected with MCMV, whereas NK cells were still activated. In turn, splenic NK cell activation was more IL-18 dependent. The differential requirements for IL-12 and IL-18 correlated with the levels of cytokine receptor expression by NK and NKT cells. Finally, mice lacking NKT cells showed reduced control of MCMV, and depleting NK cells further enhanced viral replication. Taken together, our results show that NKT and NK cells have differing requirements for cytokine-mediated activation, and both can contribute nonredundantly to MCMV defense, revealing that these two innate lymphocyte subsets function together to fine-tune antiviral responses.