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Conditional Deletion of TAK1 in T Cells Reveals a Pivotal Role of TCRαβ+ Intraepithelial Lymphocytes in Preventing Lymphopenia-Associated Colitis.

Sanjo H, Tokumaru S, Akira S, Taki S - PLoS ONE (2015)

Bottom Line: The kinase TAK is required for the development of conventional and regulatory T cells.Furthermore, the gut microbiota-triggered signaling was also a key event leading to the pathogenesis.Taken together, our current study highlighted the emerging role of TAK1 in configuring the gut-specialized T cell subset, which regulates mucosal homeostasis under lymphopenic conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Immunology, Shinshu University School of Medicine, Nagano, Japan.

ABSTRACT
The kinase TAK is required for the development of conventional and regulatory T cells. We previously reported that mice with conditional deletion of TAK1 in T cells (Lck-cre:TAK1fl/fl mice) exhibited severe T lymphopenia, and were nevertheless predisposed to spontaneous colitis with unknown etiology. Here we focused on the immunopathological mechanism in colitic Lck-cre:TAK1fl/fl mice. We found that 'leaky' CD4+ T cells retaining TAK1 acquired inflammatory phenotypes that contribute to disease onset in Lck-cre:TAK1fl/fl mice. Furthermore, the gut microbiota-triggered signaling was also a key event leading to the pathogenesis. We discovered that Lck-cre:TAK1fl/fl mice were almost completely devoid of TCRαβ+CD8α+ intestinal intraepithelial lymphocytes (IELs) and this was largely due to the developmental defect of the thymic precursors by TAK1 deficiency. Remarkably, transfer of TCRαβ+CD8α+ IELs from wild-type mice ameliorated colitis in Lck-cre:TAK1fl/fl mice. Taken together, our current study highlighted the emerging role of TAK1 in configuring the gut-specialized T cell subset, which regulates mucosal homeostasis under lymphopenic conditions.

No MeSH data available.


Related in: MedlinePlus

Administration of TCRαβ+CD8α+ IELs ameliorates spontaneous colitis in LTAC mice.Individual T cell subsets sorted from the spleen or the small and large intestine of CD45.1+ C57BL/6 mice were intravenously transferred into 6- to 8-week-old LTAC mice. Eight weeks after transfer, the mice were used for analysis. (A) HE staining with proximal colons. Data are representative of 5 to 6 individual mice. Scale bar, 200 μm. (B) Histological score determined based upon criteria for colitis is depicted in each mouse group. No transfer (–) (n = 5, filled bar), CD8+ T (n = 6, open bar), TCRαβ+CD8α+ IEL (n = 6, hatched bar), NKT cells (n = 6, vertical striped bar). Data are shown as mean ± standard error of the mean (s.e.m.). In (B), one-way analysis of variance (ANOVA) Bonferroni’s multiple comparison test was performed. Statistical significance is indicated by ***P < 0.001; ns, not significant.
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pone.0128761.g007: Administration of TCRαβ+CD8α+ IELs ameliorates spontaneous colitis in LTAC mice.Individual T cell subsets sorted from the spleen or the small and large intestine of CD45.1+ C57BL/6 mice were intravenously transferred into 6- to 8-week-old LTAC mice. Eight weeks after transfer, the mice were used for analysis. (A) HE staining with proximal colons. Data are representative of 5 to 6 individual mice. Scale bar, 200 μm. (B) Histological score determined based upon criteria for colitis is depicted in each mouse group. No transfer (–) (n = 5, filled bar), CD8+ T (n = 6, open bar), TCRαβ+CD8α+ IEL (n = 6, hatched bar), NKT cells (n = 6, vertical striped bar). Data are shown as mean ± standard error of the mean (s.e.m.). In (B), one-way analysis of variance (ANOVA) Bonferroni’s multiple comparison test was performed. Statistical significance is indicated by ***P < 0.001; ns, not significant.

Mentions: In order to further explore the relationship between the reduction of T lymphocytes and spontaneous colitis, we considered that deficiency of T cell subset(s) in LTAC mice might have an important cue to prevent the disease onset. To this end, we transferred individual T cell subsets purified from CD45.1+ C57BL/6 mice into 6- to 8-week-old LTAC mice that had not yet displayed any signs of the colitis and examined these mice for colitis 8 weeks after transfer. We observed inflammatory infiltrates and massive tissue damages, the typical features for colitis, in LTAC mice transferred with conventional CD8+ T or NKT cells as well as in untreated LTAC mice (Fig 7A and 7B). Surprisingly, when TCRαβ+CD8α+ IELs were transferred into LTAC mice, we noticed a significant amelioration of colitis (Fig 7A and 7B). Collectively, these data indicated that the lack of TCRαβ+CD8α+ IEL in the intestinal epithelial layer led to the pathogenesis of colitis in LTAC mice.


Conditional Deletion of TAK1 in T Cells Reveals a Pivotal Role of TCRαβ+ Intraepithelial Lymphocytes in Preventing Lymphopenia-Associated Colitis.

Sanjo H, Tokumaru S, Akira S, Taki S - PLoS ONE (2015)

Administration of TCRαβ+CD8α+ IELs ameliorates spontaneous colitis in LTAC mice.Individual T cell subsets sorted from the spleen or the small and large intestine of CD45.1+ C57BL/6 mice were intravenously transferred into 6- to 8-week-old LTAC mice. Eight weeks after transfer, the mice were used for analysis. (A) HE staining with proximal colons. Data are representative of 5 to 6 individual mice. Scale bar, 200 μm. (B) Histological score determined based upon criteria for colitis is depicted in each mouse group. No transfer (–) (n = 5, filled bar), CD8+ T (n = 6, open bar), TCRαβ+CD8α+ IEL (n = 6, hatched bar), NKT cells (n = 6, vertical striped bar). Data are shown as mean ± standard error of the mean (s.e.m.). In (B), one-way analysis of variance (ANOVA) Bonferroni’s multiple comparison test was performed. Statistical significance is indicated by ***P < 0.001; ns, not significant.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4489433&req=5

pone.0128761.g007: Administration of TCRαβ+CD8α+ IELs ameliorates spontaneous colitis in LTAC mice.Individual T cell subsets sorted from the spleen or the small and large intestine of CD45.1+ C57BL/6 mice were intravenously transferred into 6- to 8-week-old LTAC mice. Eight weeks after transfer, the mice were used for analysis. (A) HE staining with proximal colons. Data are representative of 5 to 6 individual mice. Scale bar, 200 μm. (B) Histological score determined based upon criteria for colitis is depicted in each mouse group. No transfer (–) (n = 5, filled bar), CD8+ T (n = 6, open bar), TCRαβ+CD8α+ IEL (n = 6, hatched bar), NKT cells (n = 6, vertical striped bar). Data are shown as mean ± standard error of the mean (s.e.m.). In (B), one-way analysis of variance (ANOVA) Bonferroni’s multiple comparison test was performed. Statistical significance is indicated by ***P < 0.001; ns, not significant.
Mentions: In order to further explore the relationship between the reduction of T lymphocytes and spontaneous colitis, we considered that deficiency of T cell subset(s) in LTAC mice might have an important cue to prevent the disease onset. To this end, we transferred individual T cell subsets purified from CD45.1+ C57BL/6 mice into 6- to 8-week-old LTAC mice that had not yet displayed any signs of the colitis and examined these mice for colitis 8 weeks after transfer. We observed inflammatory infiltrates and massive tissue damages, the typical features for colitis, in LTAC mice transferred with conventional CD8+ T or NKT cells as well as in untreated LTAC mice (Fig 7A and 7B). Surprisingly, when TCRαβ+CD8α+ IELs were transferred into LTAC mice, we noticed a significant amelioration of colitis (Fig 7A and 7B). Collectively, these data indicated that the lack of TCRαβ+CD8α+ IEL in the intestinal epithelial layer led to the pathogenesis of colitis in LTAC mice.

Bottom Line: The kinase TAK is required for the development of conventional and regulatory T cells.Furthermore, the gut microbiota-triggered signaling was also a key event leading to the pathogenesis.Taken together, our current study highlighted the emerging role of TAK1 in configuring the gut-specialized T cell subset, which regulates mucosal homeostasis under lymphopenic conditions.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cellular Immunology, Shinshu University School of Medicine, Nagano, Japan.

ABSTRACT
The kinase TAK is required for the development of conventional and regulatory T cells. We previously reported that mice with conditional deletion of TAK1 in T cells (Lck-cre:TAK1fl/fl mice) exhibited severe T lymphopenia, and were nevertheless predisposed to spontaneous colitis with unknown etiology. Here we focused on the immunopathological mechanism in colitic Lck-cre:TAK1fl/fl mice. We found that 'leaky' CD4+ T cells retaining TAK1 acquired inflammatory phenotypes that contribute to disease onset in Lck-cre:TAK1fl/fl mice. Furthermore, the gut microbiota-triggered signaling was also a key event leading to the pathogenesis. We discovered that Lck-cre:TAK1fl/fl mice were almost completely devoid of TCRαβ+CD8α+ intestinal intraepithelial lymphocytes (IELs) and this was largely due to the developmental defect of the thymic precursors by TAK1 deficiency. Remarkably, transfer of TCRαβ+CD8α+ IELs from wild-type mice ameliorated colitis in Lck-cre:TAK1fl/fl mice. Taken together, our current study highlighted the emerging role of TAK1 in configuring the gut-specialized T cell subset, which regulates mucosal homeostasis under lymphopenic conditions.

No MeSH data available.


Related in: MedlinePlus