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Clearance of HIV type 1 envelope recombinant sendai virus depends on CD4+ T cells and interferon-gamma but not B cells, CD8+ T cells, or perforin.

ABSTRACT: T cell-mediated viral clearance is classically attributed to the CD8(+) T cell subset, but CD4(+) T cells can sometimes assume this role. One such instance was illustrated by the immunization of C57BL/6 mice with HIV-1 envelope, followed by challenge with a recombinant Sendai virus (rSeV-env) carrying a gene for secreted HIV-1 envelope protein. Vaccinated mice that lacked both B cells (microMT) and CD8(+) T cells controlled virus, but control was lost when CD4(+) T cells were depleted. To explain this activity, we questioned whether CD4(+) T cells might utilize perforin for killing of MHC class II-positive targets. We also asked if the process might depend on IFN-gamma, which can upregulate MHC expression and enhance T cell recruitment to sites of virus challenge. To address these possibilities, we vaccinated perforin-KO mice with HIV-1 envelope and challenged them with rSeV-env. We found that perforin was not required for (1) CD4(+) T cell homing to the site of virus challenge, (2) expression of Th1 and Th2 cytokines (including IFN-gamma), or (3) virus clearance. To determine if IFN-gamma was required for protection, we repeated experiments in IFN-gamma-KO animals. In this case, significant protection was lost, although the CD4(+) T cells trafficked readily to the site of infection. In fact, local CD4(+) T cell numbers in vaccinated IFN-gamma- KO mice exceeded those in wild type animals. In both cases, cells were alphass TCR(+), NK-1.1(-), and CD44(+), typifying an activated CD4(+) T cell subset. Taken together, our results showed that HIV-1 envelope recombinant virus clearance was dependent on CD4(+) T cells and IFN-gamma, but occurred in the absence of B cells, CD8(+) T cells, or perforin.

SUBMITTER: Surman SL

PROVIDER: S-EPMC2932556 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Clearance of HIV type 1 envelope recombinant sendai virus depends on CD4+ T cells and interferon-gamma but not B cells, CD8+ T cells, or perforin.

Surman Sherri L SL Brown Scott A SA Jones Bart G BG Woodland David L DL Hurwitz Julia L JL

AIDS research and human retroviruses 20100701 7

T cell-mediated viral clearance is classically attributed to the CD8(+) T cell subset, but CD4(+) T cells can sometimes assume this role. One such instance was illustrated by the immunization of C57BL/6 mice with HIV-1 envelope, followed by challenge with a recombinant Sendai virus (rSeV-env) carrying a gene for secreted HIV-1 envelope protein. Vaccinated mice that lacked both B cells (microMT) and CD8(+) T cells controlled virus, but control was lost when CD4(+) T cells were depleted. To explai ...[more]

PMID: 20623995

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Project description:In Chagas disease, CD8(+) T-cells are critical for the control of Trypanosoma cruzi during acute infection. Conversely, CD8(+) T-cell accumulation in the myocardium during chronic infection may cause tissue injury leading to chronic chagasic cardiomyopathy (CCC). Here we explored the role of CD8(+) T-cells in T. cruzi-elicited heart injury in C57BL/6 mice infected with the Colombian strain. Cardiomyocyte lesion evaluated by creatine kinase-MB isoenzyme activity levels in the serum and electrical abnormalities revealed by electrocardiogram were not associated with the intensity of heart parasitism and myocarditis in the chronic infection. Further, there was no association between heart injury and systemic anti-T. cruzi CD8(+) T-cell capacity to produce interferon-gamma (IFN?) and to perform specific cytotoxicity. Heart injury, however, paralleled accumulation of anti-T. cruzi cells in the cardiac tissue. In T. cruzi infection, most of the CD8(+) T-cells segregated into IFN?(+) perforin (Pfn)(neg) or IFN?(neg)Pfn(+) cell populations. Colonization of the cardiac tissue by anti-T. cruzi CD8(+)Pfn(+) cells paralleled the worsening of CCC. The adoptive cell transfer to T. cruzi-infected cd8(-/-) recipients showed that the CD8(+) cells from infected ifn?(-/-)pfn(+/+) donors migrate towards the cardiac tissue to a greater extent and caused a more severe cardiomyocyte lesion than CD8(+) cells from ifn?(+/+)pfn(-/-) donors. Moreover, the reconstitution of naïve cd8(-/-) mice with CD8(+) cells from naïve ifn?(+/+)pfn(-/-) donors ameliorated T. cruzi-elicited heart injury paralleled IFN?(+) cells accumulation, whereas reconstitution with CD8(+) cells from naïve ifn?(-/-)pfn(+/+) donors led to an aggravation of the cardiomyocyte lesion, which was associated with the accumulation of Pfn(+) cells in the cardiac tissue. Our data support a possible antagonist effect of CD8(+)Pfn(+) and CD8(+)IFN?(+) cells during CCC. CD8(+)IFN?(+) cells may exert a beneficial role, whereas CD8(+)Pfn(+) may play a detrimental role in T. cruzi-elicited heart injury.

Project description:Evaluation of antigen-specific T-cell responses to viral antigens is frequently performed on IFN-? secreting cells. However, T-cells are capable of producing many more functions than just IFN-?, some of which, like Perforin, are associated with immune protection in HIV-1 disease elite controllers. We evaluated the extent of missed T-cell functions when IFN-? secretion is used as a surrogate marker for further evaluation of T-cell functions. Intracellular cytokine staining assay and flow cytometry were used to assess peripheral blood mononuclear cells (PBMCs) from 31 HIV-infected ART-naive individuals for the extent to which gated CD4+ and CD8+ IFN-? producing and non-producing T-cells also secreted IL-2, Perforin, and TNF-? functions. Similarly, the extent of missed virus-specific responses in IFN-? ELISpot assay negative T-cells from 5 HIV-1 uninfected individuals was evaluated. Cells from HIV-infected individuals were stimulated with pooled consensus group M (Con M) peptides; and those from healthy individuals were stimulated with pooled adenovirus (Ad) peptides. Overall, frequencies of virus-specific IFN-? secreting CD4+ and CD8+ cells were low. Proportions of IFN-? negative CD4+ expressing IL-2, Perforin, or TNF-? to Con M were significantly higher (5 of 7 functional profiles) than the corresponding IFN-? positive CD4+ (0 of 7) T-cell phenotype, p?=?0.02; Fisher's Exact test. Likewise, proportions of CD8+ T-cells expressing other functions were significantly higher in 4 of the 7 IFN-? negative CD8+ T-cells. Notably, newly stimulated Perforin, identified as Perforin co-expression with IL-2 or TNF-?, was significantly higher in IFN-? negative CD8+ T-cell than in the positive CD8+ T-cells. Using SEB, lower responses in IFN-? positive cells were most associated with CD4+ than CD8+ T-cells. These findings suggest that studies evaluating immunogenicity in response to HIV and Adenovirus viral antigens should not only evaluate T-cell responsiveness among IFN-? producing cells but also among those T-cells that do not express IFN-?.

Dataset Information

Clearance of HIV type 1 envelope recombinant sendai virus depends on CD4+ T cells and interferon-gamma but not B cells, CD8+ T cells, or perforin.

Publications

Clearance of HIV type 1 envelope recombinant sendai virus depends on CD4+ T cells and interferon-gamma but not B cells, CD8+ T cells, or perforin.

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