Publications by authors named "Douglas C Braaten"

5 Publications

  • Page 1 of 1

Specific mutation of a gammaherpesvirus-expressed antigen in response to CD8 T cell selection in vivo.

J Virol 2012 Mar 14;86(5):2887-93. Epub 2011 Dec 14.

Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

Herpesviruses are thought to be highly genetically stable, and their use as vaccine vectors has been proposed. However, studies of the human gammaherpesvirus, Epstein-Barr virus, have found viral isolates containing mutations in HLA class I-restricted epitopes. Using murine gammaherpesvirus 68 expressing ovalbumin (OVA), we examined the stability of a gammaherpesvirus antigenic locus under strong CD8 T cell selection in vivo. OVA-specific CD8 T cells selected viral isolates containing mutations in the OVA locus but minimal alterations in other genomic regions. Thus, a CD8 T cell response to a gammaherpesvirus-expressed antigen that is not essential for replication or pathogenesis can result in selective mutation of that antigen in vivo. This finding may have relevance for the use of herpesvirus vectors for chronic antigen expression in vivo.
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http://dx.doi.org/10.1128/JVI.06101-11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3302239PMC
March 2012

Effective control of chronic gamma-herpesvirus infection by unconventional MHC Class Ia-independent CD8 T cells.

PLoS Pathog 2006 May 19;2(5):e37. Epub 2006 May 19.

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

Control of virus infection is mediated in part by major histocompatibility complex (MHC) Class Ia presentation of viral peptides to conventional CD8 T cells. Although important, the absolute requirement for MHC Class Ia-dependent CD8 T cells for control of chronic virus infection has not been formally demonstrated. We show here that mice lacking MHC Class Ia molecules (K(b-/-)xD(b-/-) mice) effectively control chronic gamma-herpesvirus 68 (gammaHV68) infection via a robust expansion of beta2-microglobulin (beta2-m)-dependent, but CD1d-independent, unconventional CD8 T cells. These unconventional CD8 T cells expressed: (1) CD8alphabeta and CD3, (2) cell surface molecules associated with conventional effector/memory CD8 T cells, (3) TCRalphabeta with a significant Vbeta4, Vbeta3, and Vbeta10 bias, and (4) the key effector cytokine interferon-gamma (IFNgamma). Unconventional CD8 T cells utilized a diverse TCR repertoire, and CDR3 analysis suggests that some of that repertoire may be utilized even in the presence of conventional CD8 T cells. This is the first demonstration to our knowledge that beta2-m-dependent, but Class Ia-independent, unconventional CD8 T cells can efficiently control chronic virus infection, implicating a role for beta2-n-dependent non-classical MHC molecules in control of chronic viral infection. We speculate that similar unconventional CD8 T cells may be able to control of other chronic viral infections, especially when viruses evade immunity by inhibiting generation of Class Ia-restricted T cells.
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http://dx.doi.org/10.1371/journal.ppat.0020037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1464388PMC
May 2006

CD4 T cell control of acute and latent murine gammaherpesvirus infection requires IFNgamma.

Virology 2005 Aug;338(2):201-8

Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid Ave., Box 8118, St. Louis, MO 63110, USA.

Murine gammaherpesvirus 68 (gammaHV68, MHV-68)-specific CD4 T cells control gammaHV68 infection by reducing the frequency of latently infected cells and by inhibiting viral replication. We have previously demonstrated that CD4 T cells do not require CD8 T or B cells to control gammaHV68 replication, demonstrating a helper-independent activity of CD4 T cells during gammaHV68 infection. The effector mechanism(s) required for this helper-independent function of CD4 T cells and for the inhibition of the establishment of latency by CD4 T cells are not known. Since IFNgamma has been previously shown to be important for control of acute, latent, and persistent gammaHV68 infection, we tested the hypothesis that CD4 T cells require IFNgamma to limit gammaHV68 latency and replication. We utilized a previously described system in which T cell receptor (TCR) transgenic T cells (DO.11.10) and a recombinant virus (gammaHV68.OVA) allow for evaluation of high numbers of virus-specific CD4 T cells during both acute and latent infection. We show here that virus-specific CD4 T cells require IFNgamma for their anti-viral function in both acute and latent gammaHV68 infection. We additionally show that an in vitro derived T helper type 1 (TH1) CD4 T cell clone, which produces IFNgamma, inhibits gammaHV68 replication after adoptive transfer into RAG mice. Together, data presented here demonstrate that both CD4 T cell-mediated helper-independent control of gammaHV68 replication and inhibition of the establishment of gammaHV68 latency require IFNgamma.
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http://dx.doi.org/10.1016/j.virol.2005.05.011DOI Listing
August 2005

An optimized CD8+ T-cell response controls productive and latent gammaherpesvirus infection.

J Virol 2005 Feb;79(4):2573-83

Department of Pathology and Immunology, Washington University School of Medicine, 660 S. Euclid, Box 8118, St. Louis, MO 63110, USA.

Strategies to prime CD8(+) T cells against Murine gammaherpesvirus 68 (gammaHV68; MHV68) latency have, to date, resulted in only limited effects. While early forms of latency (<21 days) were significantly reduced, effects were not seen at later times, indicating loss of control by the primed CD8(+) T cells. In the present study, we evaluated CD8(+) T cells in an optimized system, consisting of OTI T-cell-receptor (TCR) transgenic mice, which generate clonal CD8(+) T cells specific for K(b)-SIINFEKL of OVA, and a recombinant gammaHV68 that expresses OVA (gammaHV68.OVA). Our aim was to test whether this optimized system would result in more effective control not only of acute infection but also of later forms of latent infection than was seen with previous strategies. First, we show that OTI CD8(+) T cells effectively controlled acute replication of gammaHV68.OVA in liver, lung, and spleen at 8 and 16 days after infection of OTI/RAG mice, which lack expression of B and CD4(+) T cells. However, we found that, despite eliminating detectable acute replication, the OTI CD8(+) T cells did not prevent the establishment of latency in the OTI/RAG mice. We next evaluated the effectiveness of OTI T cells in OTI/B6 animals, which express B cells--a major site of latency in wild-type mice--and CD4(+) T cells. In OTI/B6 mice OTI CD8(+) T cells not only reduced the frequency of cells that reactivate from latency and the frequency of cells bearing the viral genome at 16 days after infection (similar to what has been reported before) but also were effective at reducing latency at 42 days after infection. Together, these data show that CD8(+) T cells are sufficient, in the absence of B cells and CD4(+) T cells, for effective control of acute replication. The data also demonstrate for the first time that a strong CD8(+) T-cell response can limit long-term latent infection.
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http://dx.doi.org/10.1128/JVI.79.4.2573-2583.2005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC546552PMC
February 2005

An optimized CD4 T-cell response can control productive and latent gammaherpesvirus infection.

J Virol 2004 Jul;78(13):6827-35

Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.

CD4 T cells are important for control of infection with murine gammaherpesvirus 68 (gamma HV68), but it is not known whether CD4 T cells function via provision of help to other lymphocyte subsets, such as B cells and CD8 T cells, or have an independent antiviral function. Moreover, under conditions of natural infection, the CD4 T-cell response is not sufficient to eliminate infection. To determine the functional capacities of CD4 T cells under optimal or near-optimal conditions and to determine whether CD4 T cells can control gamma HV68 infection in the absence of CD8 T cells or B cells, we studied the effect of ovalbumin (OVA)-specific CD4 T cells on infection with a recombinant gamma HV68 that expresses OVA. OVA-specific CD4 T cells limited acute gamma HV68 replication and prolonged the life of infected T-cell receptor-transgenic RAG (DO.11.10/RAG) mice, demonstrating CD4 T-cell antiviral activity, independent of CD8 T cells and B cells. Despite CD4 T-cell-mediated control of acute infection, latent infection was established in DO.11.10/RAG mice. However, OVA-specific CD4 T cells reduced the frequency of latently infected cells both early (16 days postinfection) and late (42 days postinfection) after infection of mice containing CD8 T cells and B cells (DO.11.10 mice). These results show that OVA-specific CD4 T cells have B-cell and CD8 T-cell-independent antiviral functions in the control of acute infection and can, in the absence of preexisting CD8 T-cell or B-cell immunity, inhibit the establishment of gammaherpesvirus latency.
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http://dx.doi.org/10.1128/JVI.78.13.6827-6835.2004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC421646PMC
July 2004