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Virus-specific regulatory T cells ameliorate encephalitis by repressing effector T cell functions from priming to effector stages.

Zhao J, Zhao J, Perlman S - PLoS Pathog. (2014)

Bottom Line: In addition, M133 Tregs diminished microglia activation and decreased the number and function of Tconv in the infected brain.Thus, virus-specific Tregs inhibited pathogenic CD4 T cell responses during priming and effector stages, particularly those recognizing cognate antigen, and decreased mortality and morbidity without affecting virus clearance.These cells are more suppressive than bulk Tregs and provide a targeted approach to ameliorating immunopathological disease in infectious settings.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Iowa, Iowa City, Iowa, United States of America.

ABSTRACT
Several studies have demonstrated the presence of pathogen-specific Foxp3+ CD4 regulatory T cells (Treg) in infected animals, but little is known about where and how these cells affect the effector T cell responses and whether they are more suppressive than bulk Treg populations. We recently showed the presence of both epitope M133-specific Tregs (M133 Treg) and conventional CD4 T cells (M133 Tconv) in the brains of mice with coronavirus-induced encephalitis. Here, we provide new insights into the interactions between pathogenic Tconv and Tregs responding to the same epitope. M133 Tregs inhibited the proliferation but not initial activation of M133 Tconv in draining lymph nodes (DLN). Further, M133 Tregs inhibited migration of M133 Tconv from the DLN. In addition, M133 Tregs diminished microglia activation and decreased the number and function of Tconv in the infected brain. Thus, virus-specific Tregs inhibited pathogenic CD4 T cell responses during priming and effector stages, particularly those recognizing cognate antigen, and decreased mortality and morbidity without affecting virus clearance. These cells are more suppressive than bulk Tregs and provide a targeted approach to ameliorating immunopathological disease in infectious settings.

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M133 Tconv and Tregs exhibit differential kinetics of T-bet and cytokine expression in DCLN.Violet labeled M133 Tconv (0.75×105) or M133 Tregs (1.5×105) were transferred to Thy1 congenic mice one day prior to rJ2.2 infection. DCLN cells were pooled from six recipient mice at day 3.5 after infection. Cells were examined for T-bet expression directly ex vivo or for IFN-γ and IL-10 expression after M133 peptide stimulation. G0: generation 0, G1: generation 1, etc. Dot plots show T-bet and cytokine expression by M133 Tconv and Tregs as they proliferate. Data are representative of two independent experiments.
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ppat-1004279-g007: M133 Tconv and Tregs exhibit differential kinetics of T-bet and cytokine expression in DCLN.Violet labeled M133 Tconv (0.75×105) or M133 Tregs (1.5×105) were transferred to Thy1 congenic mice one day prior to rJ2.2 infection. DCLN cells were pooled from six recipient mice at day 3.5 after infection. Cells were examined for T-bet expression directly ex vivo or for IFN-γ and IL-10 expression after M133 peptide stimulation. G0: generation 0, G1: generation 1, etc. Dot plots show T-bet and cytokine expression by M133 Tconv and Tregs as they proliferate. Data are representative of two independent experiments.

Mentions: M133-specific Tregs in the infected brain express T-bet and several cytokines (IFN-γ, TNF and IL-10) [12]. We next sought to determine whether this differentiation to a Th1 phenotype occurred after Tregs had entered the brain, or earlier in the DCLN. We transferred either M133 Tconv or Treg into mice prior to rJ2.2 infection and measured T-bet and cytokine expression in the DCLN at day 3.5 p.i. (Figure 7). T-bet was expressed by both types of cells at this early time post infection, after either one (Tconv) or three (Treg) cell divisions. Further, IFN-γ and IL-10 were expressed by both M133 Tconv and Tregs in the DCLN after direct ex vivo stimulation with M133 peptide. Tregs required more cell divisions to express IFN-γ than Tconv but conversely, IL-10 expression by Tregs occurred after fewer cell divisions than Tconv. Thus, Treg ability to express cytokines did not require entry into the infected brain, but rather the milieu in the draining DCLN was sufficient to trigger differentiation. These cells then migrated to the infected brain, already competent for cytokine expression.


Virus-specific regulatory T cells ameliorate encephalitis by repressing effector T cell functions from priming to effector stages.

Zhao J, Zhao J, Perlman S - PLoS Pathog. (2014)

M133 Tconv and Tregs exhibit differential kinetics of T-bet and cytokine expression in DCLN.Violet labeled M133 Tconv (0.75×105) or M133 Tregs (1.5×105) were transferred to Thy1 congenic mice one day prior to rJ2.2 infection. DCLN cells were pooled from six recipient mice at day 3.5 after infection. Cells were examined for T-bet expression directly ex vivo or for IFN-γ and IL-10 expression after M133 peptide stimulation. G0: generation 0, G1: generation 1, etc. Dot plots show T-bet and cytokine expression by M133 Tconv and Tregs as they proliferate. Data are representative of two independent experiments.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4125232&req=5

ppat-1004279-g007: M133 Tconv and Tregs exhibit differential kinetics of T-bet and cytokine expression in DCLN.Violet labeled M133 Tconv (0.75×105) or M133 Tregs (1.5×105) were transferred to Thy1 congenic mice one day prior to rJ2.2 infection. DCLN cells were pooled from six recipient mice at day 3.5 after infection. Cells were examined for T-bet expression directly ex vivo or for IFN-γ and IL-10 expression after M133 peptide stimulation. G0: generation 0, G1: generation 1, etc. Dot plots show T-bet and cytokine expression by M133 Tconv and Tregs as they proliferate. Data are representative of two independent experiments.
Mentions: M133-specific Tregs in the infected brain express T-bet and several cytokines (IFN-γ, TNF and IL-10) [12]. We next sought to determine whether this differentiation to a Th1 phenotype occurred after Tregs had entered the brain, or earlier in the DCLN. We transferred either M133 Tconv or Treg into mice prior to rJ2.2 infection and measured T-bet and cytokine expression in the DCLN at day 3.5 p.i. (Figure 7). T-bet was expressed by both types of cells at this early time post infection, after either one (Tconv) or three (Treg) cell divisions. Further, IFN-γ and IL-10 were expressed by both M133 Tconv and Tregs in the DCLN after direct ex vivo stimulation with M133 peptide. Tregs required more cell divisions to express IFN-γ than Tconv but conversely, IL-10 expression by Tregs occurred after fewer cell divisions than Tconv. Thus, Treg ability to express cytokines did not require entry into the infected brain, but rather the milieu in the draining DCLN was sufficient to trigger differentiation. These cells then migrated to the infected brain, already competent for cytokine expression.

Bottom Line: In addition, M133 Tregs diminished microglia activation and decreased the number and function of Tconv in the infected brain.Thus, virus-specific Tregs inhibited pathogenic CD4 T cell responses during priming and effector stages, particularly those recognizing cognate antigen, and decreased mortality and morbidity without affecting virus clearance.These cells are more suppressive than bulk Tregs and provide a targeted approach to ameliorating immunopathological disease in infectious settings.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, University of Iowa, Iowa City, Iowa, United States of America.

ABSTRACT
Several studies have demonstrated the presence of pathogen-specific Foxp3+ CD4 regulatory T cells (Treg) in infected animals, but little is known about where and how these cells affect the effector T cell responses and whether they are more suppressive than bulk Treg populations. We recently showed the presence of both epitope M133-specific Tregs (M133 Treg) and conventional CD4 T cells (M133 Tconv) in the brains of mice with coronavirus-induced encephalitis. Here, we provide new insights into the interactions between pathogenic Tconv and Tregs responding to the same epitope. M133 Tregs inhibited the proliferation but not initial activation of M133 Tconv in draining lymph nodes (DLN). Further, M133 Tregs inhibited migration of M133 Tconv from the DLN. In addition, M133 Tregs diminished microglia activation and decreased the number and function of Tconv in the infected brain. Thus, virus-specific Tregs inhibited pathogenic CD4 T cell responses during priming and effector stages, particularly those recognizing cognate antigen, and decreased mortality and morbidity without affecting virus clearance. These cells are more suppressive than bulk Tregs and provide a targeted approach to ameliorating immunopathological disease in infectious settings.

Show MeSH
Related in: MedlinePlus