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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 Tregs modulate M133 Tconv accumulation in the DCLN, spleen and brain.(A) Experimental design. M133 Tconv alone or a mixture of M133 Tconv and bulk Tregs or M133 Tconv and M133 Tregs (1∶2 ratio) were labeled with Violet. After labeling, 0.75×105 M133 Tconv or 2.25×105 mixed cells were transferred into Thy1 congenic mice one day prior to rJ2.2 infection. (B) Numbers of M133 Tconv in DCLN, spleen and brain of recipient mice at the indicated times p.i. The data in B are representative of 3 independent experiments with 3–4 mice/time point. Asterisks indicate statistical significance when mice receiving M133 Tconv and M133 Tregs were compared to those receiving only M133 Tconv or M133 Tconv and bulk Tregs. *P<0.05, **P<0.01, ***P<0.001.
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ppat-1004279-g005: M133 Tregs modulate M133 Tconv accumulation in the DCLN, spleen and brain.(A) Experimental design. M133 Tconv alone or a mixture of M133 Tconv and bulk Tregs or M133 Tconv and M133 Tregs (1∶2 ratio) were labeled with Violet. After labeling, 0.75×105 M133 Tconv or 2.25×105 mixed cells were transferred into Thy1 congenic mice one day prior to rJ2.2 infection. (B) Numbers of M133 Tconv in DCLN, spleen and brain of recipient mice at the indicated times p.i. The data in B are representative of 3 independent experiments with 3–4 mice/time point. Asterisks indicate statistical significance when mice receiving M133 Tconv and M133 Tregs were compared to those receiving only M133 Tconv or M133 Tconv and bulk Tregs. *P<0.05, **P<0.01, ***P<0.001.

Mentions: Since M133 Tregs and Tconv expanded at the same site, we reasoned that M133 Tregs would suppress Tconv activation and proliferation if both were present in the DCLN, and that M133 Tregs would be more suppressive than bulk Tregs since the latter did not proliferate. To examine these possibilities, we transferred M133 Tconv in the presence or absence of co-transferred M133 or bulk Tregs and sacrificed them at days 3–5 p.i. (Figure 5A). Bulk Tregs had no effect on numbers of M133 Tconv in the DCLN, spleen or brain at any time (Figure 5B). In contrast, the presence of M133 Tregs resulted in decreased numbers of Tconv in the spleen and brain at all times p.i., suggesting an effect on Tconv proliferation. However, the effects of transferred M133 Tregs were more complicated in the DCLN. M133 Tconv numbers in the DCLN were increased at day 3 and 5 p.i., but decreased at day 4.


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 Tregs modulate M133 Tconv accumulation in the DCLN, spleen and brain.(A) Experimental design. M133 Tconv alone or a mixture of M133 Tconv and bulk Tregs or M133 Tconv and M133 Tregs (1∶2 ratio) were labeled with Violet. After labeling, 0.75×105 M133 Tconv or 2.25×105 mixed cells were transferred into Thy1 congenic mice one day prior to rJ2.2 infection. (B) Numbers of M133 Tconv in DCLN, spleen and brain of recipient mice at the indicated times p.i. The data in B are representative of 3 independent experiments with 3–4 mice/time point. Asterisks indicate statistical significance when mice receiving M133 Tconv and M133 Tregs were compared to those receiving only M133 Tconv or M133 Tconv and bulk Tregs. *P<0.05, **P<0.01, ***P<0.001.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1004279-g005: M133 Tregs modulate M133 Tconv accumulation in the DCLN, spleen and brain.(A) Experimental design. M133 Tconv alone or a mixture of M133 Tconv and bulk Tregs or M133 Tconv and M133 Tregs (1∶2 ratio) were labeled with Violet. After labeling, 0.75×105 M133 Tconv or 2.25×105 mixed cells were transferred into Thy1 congenic mice one day prior to rJ2.2 infection. (B) Numbers of M133 Tconv in DCLN, spleen and brain of recipient mice at the indicated times p.i. The data in B are representative of 3 independent experiments with 3–4 mice/time point. Asterisks indicate statistical significance when mice receiving M133 Tconv and M133 Tregs were compared to those receiving only M133 Tconv or M133 Tconv and bulk Tregs. *P<0.05, **P<0.01, ***P<0.001.
Mentions: Since M133 Tregs and Tconv expanded at the same site, we reasoned that M133 Tregs would suppress Tconv activation and proliferation if both were present in the DCLN, and that M133 Tregs would be more suppressive than bulk Tregs since the latter did not proliferate. To examine these possibilities, we transferred M133 Tconv in the presence or absence of co-transferred M133 or bulk Tregs and sacrificed them at days 3–5 p.i. (Figure 5A). Bulk Tregs had no effect on numbers of M133 Tconv in the DCLN, spleen or brain at any time (Figure 5B). In contrast, the presence of M133 Tregs resulted in decreased numbers of Tconv in the spleen and brain at all times p.i., suggesting an effect on Tconv proliferation. However, the effects of transferred M133 Tregs were more complicated in the DCLN. M133 Tconv numbers in the DCLN were increased at day 3 and 5 p.i., but decreased at day 4.

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