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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 Treg proliferation occurs in DCLN and CLN after FTY720 treatment.(A) Experimental design. M133 Tregs and M133 Tconv were mixed at a 1∶1 ratio and labeled with Violet. 1.5×105 cells were transferred to Thy1 congenic mice one day prior to infection with rJ2.2. Mice were treated with FTY720 or saline 0.5 hour prior to infection and on days 1, 2, 3 p.i. (B) Representative plots showing Violet dilution at day 4 p.i. Numbers are percentage of divided Tregs (upper) or Tconv (lower). (C) Summary of data from three independent experiments with three mice in each.
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ppat-1004279-g004: M133 Tconv and Treg proliferation occurs in DCLN and CLN after FTY720 treatment.(A) Experimental design. M133 Tregs and M133 Tconv were mixed at a 1∶1 ratio and labeled with Violet. 1.5×105 cells were transferred to Thy1 congenic mice one day prior to infection with rJ2.2. Mice were treated with FTY720 or saline 0.5 hour prior to infection and on days 1, 2, 3 p.i. (B) Representative plots showing Violet dilution at day 4 p.i. Numbers are percentage of divided Tregs (upper) or Tconv (lower). (C) Summary of data from three independent experiments with three mice in each.

Mentions: To confirm the DCLN as the site of proliferation of Tconv and determine whether Tregs were also primed at this site, we transferred Violet-labeled M133-specific Tconv and Tregs in a 1∶2 ratio to mice one day prior to infection (Figure 3A). This resulted in a 1∶1 ratio because only 50% of Tregs were M133-specific (Figure 1A). Cells were analyzed at days 2–4 instead of days 3–5 to capture early cell proliferation, since we had observed substantial proliferation of Tconv in the DCLN by day 3 p.i. when only Tconv were transferred (Figure 2B). By day 2 p.i, we observed five generations (4 divisions) of Violet-labeled Tconv in the DCLN but not other tissues. In contrast, Treg proliferation was not detected until day 3 p.i. with Violet dilution occurring initially in the DCLN (Figure 3B). By day 4 p.i., M133 Tconv and Tregs that had undergone extensive division were detected in the DCLN and CLN, with Tconv proliferation occurring to a greater extent than that of Tregs. This resulted in a dramatic increase in the ratio of Tconv to Tregs from day 3 to 4 p.i. in the DCLN and CLN (Figure 3C). Of note, only very few M133 CD4 T cells entered the brain at days 3 or 4 p.i., but remarkably, the majority of these cells were Tregs (Figure 3D). Tregs were able to enter the brain after fewer cycles of proliferation when compared to Tconv (Figure 3Dand4B). Exposure to M133 antigen was required for proliferation because neither M133 Tconv nor M133 Treg proliferated in mice infected with a rJ2.2 mutant (rJ2.2.MY135Q) in which epitope M133 expression was abrogated (Figure 3E). Similar to M133 Tconv, we detected CXCR3 expression on M133 Tregs within 1–2 generations of division (Figure 3F).


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 Treg proliferation occurs in DCLN and CLN after FTY720 treatment.(A) Experimental design. M133 Tregs and M133 Tconv were mixed at a 1∶1 ratio and labeled with Violet. 1.5×105 cells were transferred to Thy1 congenic mice one day prior to infection with rJ2.2. Mice were treated with FTY720 or saline 0.5 hour prior to infection and on days 1, 2, 3 p.i. (B) Representative plots showing Violet dilution at day 4 p.i. Numbers are percentage of divided Tregs (upper) or Tconv (lower). (C) Summary of data from three independent experiments with three mice in each.
© Copyright Policy
Related In: Results  -  Collection

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ppat-1004279-g004: M133 Tconv and Treg proliferation occurs in DCLN and CLN after FTY720 treatment.(A) Experimental design. M133 Tregs and M133 Tconv were mixed at a 1∶1 ratio and labeled with Violet. 1.5×105 cells were transferred to Thy1 congenic mice one day prior to infection with rJ2.2. Mice were treated with FTY720 or saline 0.5 hour prior to infection and on days 1, 2, 3 p.i. (B) Representative plots showing Violet dilution at day 4 p.i. Numbers are percentage of divided Tregs (upper) or Tconv (lower). (C) Summary of data from three independent experiments with three mice in each.
Mentions: To confirm the DCLN as the site of proliferation of Tconv and determine whether Tregs were also primed at this site, we transferred Violet-labeled M133-specific Tconv and Tregs in a 1∶2 ratio to mice one day prior to infection (Figure 3A). This resulted in a 1∶1 ratio because only 50% of Tregs were M133-specific (Figure 1A). Cells were analyzed at days 2–4 instead of days 3–5 to capture early cell proliferation, since we had observed substantial proliferation of Tconv in the DCLN by day 3 p.i. when only Tconv were transferred (Figure 2B). By day 2 p.i, we observed five generations (4 divisions) of Violet-labeled Tconv in the DCLN but not other tissues. In contrast, Treg proliferation was not detected until day 3 p.i. with Violet dilution occurring initially in the DCLN (Figure 3B). By day 4 p.i., M133 Tconv and Tregs that had undergone extensive division were detected in the DCLN and CLN, with Tconv proliferation occurring to a greater extent than that of Tregs. This resulted in a dramatic increase in the ratio of Tconv to Tregs from day 3 to 4 p.i. in the DCLN and CLN (Figure 3C). Of note, only very few M133 CD4 T cells entered the brain at days 3 or 4 p.i., but remarkably, the majority of these cells were Tregs (Figure 3D). Tregs were able to enter the brain after fewer cycles of proliferation when compared to Tconv (Figure 3Dand4B). Exposure to M133 antigen was required for proliferation because neither M133 Tconv nor M133 Treg proliferated in mice infected with a rJ2.2 mutant (rJ2.2.MY135Q) in which epitope M133 expression was abrogated (Figure 3E). Similar to M133 Tconv, we detected CXCR3 expression on M133 Tregs within 1–2 generations of division (Figure 3F).

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