Limits...
Impact of the TCR signal on regulatory T cell homeostasis, function, and trafficking.

Kim JK, Klinger M, Benjamin J, Xiao Y, Erle DJ, Littman DR, Killeen N - PLoS ONE (2009)

Bottom Line: Using an Ox40-cre allele that is prominently expressed in Treg cells, and a conditional allele of the gene encoding p56(Lck), we have examined the importance of TCR signaling in Treg cells.Inactivation of p56(Lck) resulted in abnormal Treg homeostasis characterized by impaired turnover, preferential redistribution to the lymph nodes, loss of suppressive function, and striking changes in gene expression.Abnormal Treg cell homeostasis and function did not reflect the involvement of p56(Lck) in CD4 function because these effects were not observed when CD4 expression was inactivated by Ox40-cre.The results make clear multiple aspects of Treg cell homeostasis and phenotype that are dependent on a sustained capacity to signal through the TCR.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA.

ABSTRACT
Signaling through the T cell antigen receptor (TCR) is important for the homeostasis of naïve and memory CD4(+) T cells. The significance of TCR signaling in regulatory T (Treg) cells has not been systematically addressed. Using an Ox40-cre allele that is prominently expressed in Treg cells, and a conditional allele of the gene encoding p56(Lck), we have examined the importance of TCR signaling in Treg cells. Inactivation of p56(Lck) resulted in abnormal Treg homeostasis characterized by impaired turnover, preferential redistribution to the lymph nodes, loss of suppressive function, and striking changes in gene expression. Abnormal Treg cell homeostasis and function did not reflect the involvement of p56(Lck) in CD4 function because these effects were not observed when CD4 expression was inactivated by Ox40-cre.The results make clear multiple aspects of Treg cell homeostasis and phenotype that are dependent on a sustained capacity to signal through the TCR.

Show MeSH
Activity of Ox40-cre in regulatory T cells.A. Thymic and lymph node expression of YFP in Ox40-cre/YFP mice (i.e., Ox40-cre mice carrying a ROSA26-loxP-STOP-loxP-YFP allele). The contour plots show that YFP expression is predominantly found on CD4+CD8− cells in both tissues (as determined by flow cytometry). FoxP3+ cells are enriched 30–40 fold in the YFP+CD4+CD8−population compared to YFP− cells. B. Penetrance of Ox40-cre recombination in CD4+CD8−CD25+ cells in the lymph nodes and thymus. The histograms show the frequency of YFP expression in regulatory phenotype cells in both tissues of Ox40-cre/YFP mice. C. Developmental stage-specific activity of Ox40-cre in the thymus. The plots show YFP expression is predominantly found in cells that are CD4+CD8− and is barely detectable at the CD4+CD8+ stage.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2719063&req=5

pone-0006580-g001: Activity of Ox40-cre in regulatory T cells.A. Thymic and lymph node expression of YFP in Ox40-cre/YFP mice (i.e., Ox40-cre mice carrying a ROSA26-loxP-STOP-loxP-YFP allele). The contour plots show that YFP expression is predominantly found on CD4+CD8− cells in both tissues (as determined by flow cytometry). FoxP3+ cells are enriched 30–40 fold in the YFP+CD4+CD8−population compared to YFP− cells. B. Penetrance of Ox40-cre recombination in CD4+CD8−CD25+ cells in the lymph nodes and thymus. The histograms show the frequency of YFP expression in regulatory phenotype cells in both tissues of Ox40-cre/YFP mice. C. Developmental stage-specific activity of Ox40-cre in the thymus. The plots show YFP expression is predominantly found in cells that are CD4+CD8− and is barely detectable at the CD4+CD8+ stage.

Mentions: Ox40-cre is an allele of the Ox40 gene that expresses the Cre recombinase in place of OX40 [25]. To determine which cells undergo Cre recombination in Ox40-cre mice, we crossed them to mice carrying a Cre-activated ROSA26-YFP reporter allele [26]. 98% of peripheral T cells that had undergone recombination and become YFP+ in such mice were CD4+ (Figure 1A), and among these one-third to one-half were FoxP3+ depending on age at the time of analysis. Strikingly, approximately 90% of lymph node or spleen CD25+ T cells were YFP+ indicating that Ox40-cre is highly efficient at inducing recombination in the regulatory lineage (Figure 1B).


Impact of the TCR signal on regulatory T cell homeostasis, function, and trafficking.

Kim JK, Klinger M, Benjamin J, Xiao Y, Erle DJ, Littman DR, Killeen N - PLoS ONE (2009)

Activity of Ox40-cre in regulatory T cells.A. Thymic and lymph node expression of YFP in Ox40-cre/YFP mice (i.e., Ox40-cre mice carrying a ROSA26-loxP-STOP-loxP-YFP allele). The contour plots show that YFP expression is predominantly found on CD4+CD8− cells in both tissues (as determined by flow cytometry). FoxP3+ cells are enriched 30–40 fold in the YFP+CD4+CD8−population compared to YFP− cells. B. Penetrance of Ox40-cre recombination in CD4+CD8−CD25+ cells in the lymph nodes and thymus. The histograms show the frequency of YFP expression in regulatory phenotype cells in both tissues of Ox40-cre/YFP mice. C. Developmental stage-specific activity of Ox40-cre in the thymus. The plots show YFP expression is predominantly found in cells that are CD4+CD8− and is barely detectable at the CD4+CD8+ stage.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2719063&req=5

pone-0006580-g001: Activity of Ox40-cre in regulatory T cells.A. Thymic and lymph node expression of YFP in Ox40-cre/YFP mice (i.e., Ox40-cre mice carrying a ROSA26-loxP-STOP-loxP-YFP allele). The contour plots show that YFP expression is predominantly found on CD4+CD8− cells in both tissues (as determined by flow cytometry). FoxP3+ cells are enriched 30–40 fold in the YFP+CD4+CD8−population compared to YFP− cells. B. Penetrance of Ox40-cre recombination in CD4+CD8−CD25+ cells in the lymph nodes and thymus. The histograms show the frequency of YFP expression in regulatory phenotype cells in both tissues of Ox40-cre/YFP mice. C. Developmental stage-specific activity of Ox40-cre in the thymus. The plots show YFP expression is predominantly found in cells that are CD4+CD8− and is barely detectable at the CD4+CD8+ stage.
Mentions: Ox40-cre is an allele of the Ox40 gene that expresses the Cre recombinase in place of OX40 [25]. To determine which cells undergo Cre recombination in Ox40-cre mice, we crossed them to mice carrying a Cre-activated ROSA26-YFP reporter allele [26]. 98% of peripheral T cells that had undergone recombination and become YFP+ in such mice were CD4+ (Figure 1A), and among these one-third to one-half were FoxP3+ depending on age at the time of analysis. Strikingly, approximately 90% of lymph node or spleen CD25+ T cells were YFP+ indicating that Ox40-cre is highly efficient at inducing recombination in the regulatory lineage (Figure 1B).

Bottom Line: Using an Ox40-cre allele that is prominently expressed in Treg cells, and a conditional allele of the gene encoding p56(Lck), we have examined the importance of TCR signaling in Treg cells.Inactivation of p56(Lck) resulted in abnormal Treg homeostasis characterized by impaired turnover, preferential redistribution to the lymph nodes, loss of suppressive function, and striking changes in gene expression.Abnormal Treg cell homeostasis and function did not reflect the involvement of p56(Lck) in CD4 function because these effects were not observed when CD4 expression was inactivated by Ox40-cre.The results make clear multiple aspects of Treg cell homeostasis and phenotype that are dependent on a sustained capacity to signal through the TCR.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, University of California San Francisco, San Francisco, CA, USA.

ABSTRACT
Signaling through the T cell antigen receptor (TCR) is important for the homeostasis of naïve and memory CD4(+) T cells. The significance of TCR signaling in regulatory T (Treg) cells has not been systematically addressed. Using an Ox40-cre allele that is prominently expressed in Treg cells, and a conditional allele of the gene encoding p56(Lck), we have examined the importance of TCR signaling in Treg cells. Inactivation of p56(Lck) resulted in abnormal Treg homeostasis characterized by impaired turnover, preferential redistribution to the lymph nodes, loss of suppressive function, and striking changes in gene expression. Abnormal Treg cell homeostasis and function did not reflect the involvement of p56(Lck) in CD4 function because these effects were not observed when CD4 expression was inactivated by Ox40-cre.The results make clear multiple aspects of Treg cell homeostasis and phenotype that are dependent on a sustained capacity to signal through the TCR.

Show MeSH