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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.

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Phenotype of p56Lck-deficient T cells.Flow cytometry data showing expression of the indicated molecules on CD25+ or CD25− lymph node CD4+ T cells from Lck/Fyn mice. Cells were permeabilized and stained with the 1F6 antibody to discriminate cells that had undergone Ox40-cre-mediated inactivation of the Lck gene from those that had not (open versus solid curve respectively).
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pone-0006580-g005: Phenotype of p56Lck-deficient T cells.Flow cytometry data showing expression of the indicated molecules on CD25+ or CD25− lymph node CD4+ T cells from Lck/Fyn mice. Cells were permeabilized and stained with the 1F6 antibody to discriminate cells that had undergone Ox40-cre-mediated inactivation of the Lck gene from those that had not (open versus solid curve respectively).

Mentions: Although p56Lck-deficient Treg cells remained positive for FoxP3 and CD25 expression, we considered it likely that the loss of TCR signaling would incur changes in gene expression. This might be predicted if the TCR signal is important for maintaining the differentiated state of the cells, and would also follow from prior data showing that tonic TCR signaling regulates expression of numerous genes in T cells [34]. By flow cytometry, we noted multiple changes in the expression of molecules known to be regulated by TCR signaling such as GITR, CD69, CD44, CD62L and CTLA4 (Figure 5). CD4 expression was also reduced, consistent with the known involvement of p56Lck in reducing the rate of CD4 endocytosis [35], [36].


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)

Phenotype of p56Lck-deficient T cells.Flow cytometry data showing expression of the indicated molecules on CD25+ or CD25− lymph node CD4+ T cells from Lck/Fyn mice. Cells were permeabilized and stained with the 1F6 antibody to discriminate cells that had undergone Ox40-cre-mediated inactivation of the Lck gene from those that had not (open versus solid curve respectively).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0006580-g005: Phenotype of p56Lck-deficient T cells.Flow cytometry data showing expression of the indicated molecules on CD25+ or CD25− lymph node CD4+ T cells from Lck/Fyn mice. Cells were permeabilized and stained with the 1F6 antibody to discriminate cells that had undergone Ox40-cre-mediated inactivation of the Lck gene from those that had not (open versus solid curve respectively).
Mentions: Although p56Lck-deficient Treg cells remained positive for FoxP3 and CD25 expression, we considered it likely that the loss of TCR signaling would incur changes in gene expression. This might be predicted if the TCR signal is important for maintaining the differentiated state of the cells, and would also follow from prior data showing that tonic TCR signaling regulates expression of numerous genes in T cells [34]. By flow cytometry, we noted multiple changes in the expression of molecules known to be regulated by TCR signaling such as GITR, CD69, CD44, CD62L and CTLA4 (Figure 5). CD4 expression was also reduced, consistent with the known involvement of p56Lck in reducing the rate of CD4 endocytosis [35], [36].

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