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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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Initial proliferation of M133 Tconv occurs in the DCLN.(A) Experimental design. 1×105 CFSE labeled M133 Tconv (Treg-depleted CD4 T cells) were transferred to Thy1 congenic mice one day prior to rJ2.2 infection. (B) Representative plots showing proliferation of transferred cells and CXCR3 expression. (C) CFSE levels on transferred cells at several times p.i. MFI, mean fluorescence intensity. (D, E) Frequency (D) and numbers (E) of M133 Tconv at the indicated times after infection. The data are representative of four independent experiments with 3 mice per time point in each.
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ppat-1004279-g002: Initial proliferation of M133 Tconv occurs in the DCLN.(A) Experimental design. 1×105 CFSE labeled M133 Tconv (Treg-depleted CD4 T cells) were transferred to Thy1 congenic mice one day prior to rJ2.2 infection. (B) Representative plots showing proliferation of transferred cells and CXCR3 expression. (C) CFSE levels on transferred cells at several times p.i. MFI, mean fluorescence intensity. (D, E) Frequency (D) and numbers (E) of M133 Tconv at the indicated times after infection. The data are representative of four independent experiments with 3 mice per time point in each.

Mentions: To identify the site of initial priming and expansion of M133 Tregs compared to Tconv, we first analyzed priming of M133 Tconv (Treg-depleted CD4 T cells) by transferring CFSE-labeled cells one day prior to infection (Figure 2A). Mice were sacrificed at days 3, 4 and 5 p.i. and analyzed for CFSE dilution (indicative of cell division) and for CXCR3 expression (required for T cell migration to the inflamed brain [24]) by M133 Tconv in the spleen, CLN, DCLN, inguinal lymph nodes (ILN) and brain. CFSE dilution occurred initially in the DCLN (Figure 2, B and C). Expression of CXCR3 was upregulated within 1–2 rounds of proliferation (Figure 2B). By day 4 p.i., M133 Tconv accounted for 10% of all CD4 T cells in the DCLN, a frequency higher than in any other lymphoid tissues that were examined (Figure 2D). While the numbers of M133 Tconvs decreased dramatically between days 4 and 5 p.i. in the DCLN (Figure 2E), they continued to increase in other lymphoid tissues. These results suggested that M133 Tconvs were primed in the DCLN and migrated to other sites. By day 5, cells that had undergone varying numbers of divisions were detected in all tissues except the brain, where only highly divided cells (complete loss of CFSE labeling) were present.


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)

Initial proliferation of M133 Tconv occurs in the DCLN.(A) Experimental design. 1×105 CFSE labeled M133 Tconv (Treg-depleted CD4 T cells) were transferred to Thy1 congenic mice one day prior to rJ2.2 infection. (B) Representative plots showing proliferation of transferred cells and CXCR3 expression. (C) CFSE levels on transferred cells at several times p.i. MFI, mean fluorescence intensity. (D, E) Frequency (D) and numbers (E) of M133 Tconv at the indicated times after infection. The data are representative of four independent experiments with 3 mice per time point in each.
© Copyright Policy
Related In: Results  -  Collection

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

ppat-1004279-g002: Initial proliferation of M133 Tconv occurs in the DCLN.(A) Experimental design. 1×105 CFSE labeled M133 Tconv (Treg-depleted CD4 T cells) were transferred to Thy1 congenic mice one day prior to rJ2.2 infection. (B) Representative plots showing proliferation of transferred cells and CXCR3 expression. (C) CFSE levels on transferred cells at several times p.i. MFI, mean fluorescence intensity. (D, E) Frequency (D) and numbers (E) of M133 Tconv at the indicated times after infection. The data are representative of four independent experiments with 3 mice per time point in each.
Mentions: To identify the site of initial priming and expansion of M133 Tregs compared to Tconv, we first analyzed priming of M133 Tconv (Treg-depleted CD4 T cells) by transferring CFSE-labeled cells one day prior to infection (Figure 2A). Mice were sacrificed at days 3, 4 and 5 p.i. and analyzed for CFSE dilution (indicative of cell division) and for CXCR3 expression (required for T cell migration to the inflamed brain [24]) by M133 Tconv in the spleen, CLN, DCLN, inguinal lymph nodes (ILN) and brain. CFSE dilution occurred initially in the DCLN (Figure 2, B and C). Expression of CXCR3 was upregulated within 1–2 rounds of proliferation (Figure 2B). By day 4 p.i., M133 Tconv accounted for 10% of all CD4 T cells in the DCLN, a frequency higher than in any other lymphoid tissues that were examined (Figure 2D). While the numbers of M133 Tconvs decreased dramatically between days 4 and 5 p.i. in the DCLN (Figure 2E), they continued to increase in other lymphoid tissues. These results suggested that M133 Tconvs were primed in the DCLN and migrated to other sites. By day 5, cells that had undergone varying numbers of divisions were detected in all tissues except the brain, where only highly divided cells (complete loss of CFSE labeling) were present.

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