Numbers Of Virus-specific CD8 Research Articles

Impaired T cell activation resulting from IL-33 induced myeloid derived suppressor cells and IL-10 secreting Tregs is a major determinant of susceptibility to HSV1 infection of the central nervous system

Abstract Resolution of viral infections of the central nervous system (CNS) is contingent on eliciting protective immunity with minimal pathology. C57BL/6 (B6) mice elucidate efficient innate and anti-viral T cell responses which render them resistant to infection with a virulent HSV 17+ virus strain. Virus replication is limited to ganglia and brainstem. However, susceptible mice such as 129S6 and BALB/c mice harbor increased virus in the CNS. These mice show increased myeloid derived suppressor cells (MDSC) and Tregs along with associated cytokines such as G-CSF, GM-CSF, IL-10 and IL-33 resulting in reduced numbers of virus specific CD8 T cells and effector T cells with increased expression of suppressive markers such as PD-1 and LAG-3. This impaired immune response resulted in disease and mortality. Neutralization of checkpoint inhibitors or immunosuppressive cytokines and depletion of myeloid cells or Tregs did not alter susceptibility rates. However, reducing expression of IL-33 in the CNS had a beneficial effect on T cell activation and the overall outcome of disease. Intriguingly, immunizing susceptible mice with a HSV thymidine kinase mutant virus incapable of infecting CNS induced memory T cells that suppressed MDSCs and protected from a subsequent challenge with HSV 17+. Interestingly IFNg, B cells or antibody were not essential but instead revealed the importance of the T cell myeloid interaction in determining disease outcomes. IL-33 plays critical roles as an immune-modulatory Th2 cytokine regulating immune-mediated diseases and tissue function especially in the CNS and as an alarmin in response to pathogens. This study shows that tempering IL-33 responses is essential to predicting improved outcomes to CNS viral infections.

The intrinsic role of ROG in CD8+ T cell development has an impact on protective immunity against viral infection (P1452)

Abstract Repressor of GATA3 (ROG) is a member of the poxviruses and zinc finger family of transcriptional repressors, and is also known as ZBTB32. Several studies have suggested that ROG may regulate the activation and differentiation CD4+ and CD8+ T cells, and further, may also play a role in plasma cell differentiation. We have investigated the role of ROG in the development of anti-viral memory T cells. Upon acute infection with LCMV Armstrong, Rog-/- mouse accumulated higher proportions and numbers of virus-specific CD8+ T cells, resulting in an increased number of memory cells. Rog-/- mouse exhibited normal viral clearance, but as a consequence of the elevated primary response, the Rog-/- CD8+ T cell population contains enhanced protective memory potential. We also examined the response of Rog-/- mice to infection with a high dose of LCMV-clone 13, which causes a chronic infection leading to exhaustion of the CD8+ T cells. We found that approximately one-half of Rog-/- mice infected with high dose LCMV-clone 13 succumbed to this infection as early as day 9 post-infection and also exhibited severe immune pathology in the lung compared to WT mice. The higher frequency of IFNg-producing virus-specific CD8+ T cells in Rog-/- mice also resulted in enhanced viral control following LCMV-clone 13 infection. These data indicate that ROG plays a unique non-redundant role during acute and chronic LCMV infection, and is an important regulator of CD8+ effector and memory T cell generation.

Cell-intrinsic Transforming Growth Factor-β signaling mediates virus-specific CD8+ T cell deletion and viral persistence in vivo (39.12)

Abstract Chronic viral infections represent a major biomedical problem. Although, in both humans and mice, viral persistence has been associated with insufficient numbers and/or function of CD8+ T cells, the underlying mechanisms are still unclear. By using Lymphocytic choriomeningitis virus in its natural murine host, we found that enhanced and sustained Transforming Growth Factor-β (TGF- β),expression and phosphorylation of its signaling mediator, Smad-2, were distinctive features of virus-specific CD8+ T cells during chronic versus acute viral infections in vivo. Selective attenuation of TGF-β pathway in T cells decreased the expression of the pro-apoptotic protein Bim and increased survival and numbers of virus-specific CD8+ T cells. Under these conditions, virus-specific CD8+ T cells had enhanced cytotoxicity, increased production of anti-viral cytokines, and down-regulation of inhibitory molecules. The end result was rapid virus eradication and generation of an effective memory T cell response that protected the host upon subsequent challenge. Notably, we found that cell-intrinsic TGF-β signaling was responsible for virus-specific-CD8+ T cell apoptosis but was not necessary for their functional exhaustion. Our findings demonstrate that sustained TGF-β-Smad signaling is a hallmark and master regulator of CD8+ T cell responses during chronic viral infections in vivo.

TCR Down-Regulation Controls Virus-Specific CD8+ T Cell Responses

The CD3gamma di-leucine-based motif plays a central role in TCR down-regulation. However, little is understood about the role of the CD3gamma di-leucine-based motif in physiological T cell responses. In this study, we show that the expansion in numbers of virus-specific CD8(+) T cells is impaired in mice with a mutated CD3gamma di-leucine-based motif. The CD3gamma mutation did not impair early TCR signaling, nor did it compromise recruitment or proliferation of virus-specific T cells, but it increased the apoptosis rate of the activated T cells by increasing down-regulation of the antiapoptotic molecule Bcl-2. This resulted in a 2-fold reduction in the clonal expansion of virus-specific CD8(+) T cells during the acute phase of vesicular stomatitis virus and lymphocytic choriomeningitis virus infections. These results identify an important role of CD3gamma-mediated TCR down-regulation in virus-specific CD8(+) T cell responses.

Age-associated decreases in influenza-specific CD8+ T cell immunity and the effect of androgen removal (B18)

Abstract Age-associated decreases in the CD8+ T cell primary and secondary responses of mice to influenza A virus infection were examined by comparing young (2 months) and aged (22–24 months) C57BL/6 mice. A significant age-associated decrease was seen in both the percentage and number of virus-specific CD8+ T cells following both primary and secondary infection. In both age groups there was a strong correlation between influenza peptide-specific tetramer+ and IFNg+ cells. Clearance of virus from the lungs, following primary infection corresponded with the time point at which maximal levels of both percentages and numbers of virus-specific CD8+ T cells were seen for both age groups. There was a delay in the maximal expansion of virus-specific CD8+ T cells in the aged mice compared to young mice following primary infection and a corresponding delay in viral clearance. A significant age-associated decrease in the cytotoxic activity was seen. Cytotoxic activity was closely correlated with the numbers of virus-specific CD8+ T cells suggesting that the age-associated problems with CD8+ T cell activity against influenza are due to decreased numbers of cells able to respond initially or a defect in expansion of these cells once exposed to the virus, rather than effector activity on a per cell basis. This was further supported by the fact that following thymic regeneration, caused by castration, there was an increase in the numbers of naïve T cells in the periphery of aged-mice with a consequent increase in the numbers of virus-specific cells and an increased ability to clear virus.

A Regulatory Effect of Tax

IMMUNOLOGY Regulatory T (T-reg) cells are central moderators of the immune system, restraining overexuberant T cells and those that have a tendency to react against the body's own components. Consequently, perturbing the function of T-reg cells could have deleterious effects on the health of an individual. Yamano et al. have extended previous observations that T-reg cells represent a preferential reservoir for the human T cell lymphotrophic virus (HTLV-1) in infected individuals. These patients develop an immunity-based neurologic disease, in which large numbers of virus-specific CD8+ cytotoxic T cells invade the central nervous system. Virus-infected T-reg cells were severely diminished in their ability to suppress T cell responses and in the expression of the transcription factor Foxp3. These deficits were traced to the expression of a viral transcriptional repressor, Tax, and could be recapitulated by transfecting the tax gene into uninfected T-reg cells. Although some autoimmune effects have been reported in this group of HTLV-1 patients, it is interesting that such a profound T-reg cell defect does not appear to result in a broader impairment of normal immune function. — SJS J. Clin. Invest. 115 , 1361 (2005).

Complexity of CNC transcription factors as revealed by gene targeting of the Nrf3 locus.

Cap'n'collar (CNC) family basic leucine zipper transcription factors play crucial roles in the regulation of mammalian gene expression and development. To determine the in vivo function of the CNC protein Nrf3 (NF-E2-related factor 3), we generated mice deficient in this transcription factor. We performed targeted disruption of two Nrf3 exons coding for CNC homology, basic DNA-binding, and leucine zipper dimerization domains. Nrf3 null mice developed normally and revealed no obvious phenotypic differences compared to wild-type animals. Nrf3(-/-) mice were fertile, and gross anatomy as well as behavior appeared normal. The mice showed normal age progression and did not show any apparent additional phenotype during their life span. We observed no differences in various blood parameters and chemistry values. We infected wild-type and Nrf3(-/-) mice with acute lymphocytic choriomeningitis virus and found no differences in these animals with respect to their number of virus-specific CD8 and CD4 T cells as well as their B-lymphocyte response. To determine whether the mild phenotype of Nrf3 null animals is due to functional redundancy, we generated mice deficient in multiple CNC factors. Contrary to our expectations, an absence of Nrf3 does not seem to cause additional lethality in compound Nrf3(-/-)/Nrf2(-/-) and Nrf3(-/-)/p45(-/-) mice. We hypothesize that the role of Nrf3 in vivo may become apparent only after appropriate challenge to the mice.

Accessing Complexity: The Dynamics of Virus-Specific T Cell Responses

The cellular dynamics of the immune system are complex and difficult to measure. Access to this problematic area has been greatly enhanced by the recent development of tetrameric complexes of MHC class I glycoprotein + peptide (tetramers) for the direct staining of freshly isolated, antigen-specific CD8(+ )T cells. Analysis to date with both naturally acquired and experimentally induced infections has established that the numbers of virus-specific CD8(+) T cells present during both the acute and memory phases of the host response are more than tenfold in excess of previously suspected values. The levels are such that the virus-specific CD8(+) set is readily detected in the human peripheral blood lymphocyte compartment, particularly during persistent infections. Experimentally, it is now possible to measure the extent of cycling for tetramer (+)CD8(+) T cells during the acute and memory phases of the host response to viruses. Dissection of the phenotypic, functional, and molecular diversity of CD8(+) T cell populations has been greatly facilitated. It is hoped it will also soon be possible to analyze CD4(+) T cell populations in this way. Though these are early days and there is an enormous amount to be done, our perceptions of the shape of virus-specific cell-mediated immunity are changing rapidly.