Limits...
TAP1-deficiency does not alter atherosclerosis development in Apoe-/- mice.

Kolbus D, Ljungcrantz I, Söderberg I, Alm R, Björkbacka H, Nilsson J, Fredrikson GN - PLoS ONE (2012)

Bottom Line: Antigen presenting cells (APC) have the ability to present both extra-cellular and intra-cellular antigens via MHC class I molecules to CD8(+) T cells.The cross presentation of extra-cellular antigens is reduced in mice with deficient Antigen Peptide Transporter 1 (TAP1)-dependent MHC class I antigen presentation, and these mice are characterized by a diminished CD8(+) T cell population.Interestingly, the fraction of CD8(+) effector memory T cells was increased but this appeared to have little impact on the atherosclerosis development.In conclusion, Apoe(-/-)Tap1(-/-) mice develop atherosclerosis equal to Apoe(-/-) mice, indicating a minor role for CD8(+) T cells and TAP1-dependent antigen presentation in the disease process.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Sciences, Skane University Hospital Malmö, Lund University, Malmö, Sweden.

ABSTRACT
Antigen presenting cells (APC) have the ability to present both extra-cellular and intra-cellular antigens via MHC class I molecules to CD8(+) T cells. The cross presentation of extra-cellular antigens is reduced in mice with deficient Antigen Peptide Transporter 1 (TAP1)-dependent MHC class I antigen presentation, and these mice are characterized by a diminished CD8(+) T cell population. We have recently reported an increased activation of CD8(+) T cells in hypercholesterolemic Apoe(-/-) mice. Therefore, this study included TAP1-deficient Apoe(-/-) mice (Apoe(-/-)Tap1(-/-)) to test the atherogenicity of CD8(+) T cells and TAP1-dependent cross presentation in a hypercholesterolemic environment. As expected the CD8(+) T cell numbers were low in Apoe(-/-)Tap1(-/-) mice in comparison to Apoe(-/-) mice, constituting ~1% of the lymphocyte population. In spite of this there were no differences in the extent of atherosclerosis as assessed by en face Oil Red O staining of the aorta and cross-sections of the aortic root between Apoe(-/-)Tap1(-/-) and Apoe(-/-) mice. Moreover, no differences were detected in lesion infiltration of macrophages or CD3(+) T cells in Apoe(-/-)Tap1(-/-) compared to Apoe(-/-) mice. The CD3(+)CD4(+) T cell fraction was increased in Apoe(-/-)Tap1(-/-) mice, suggesting a compensation for the decreased CD8(+) T cell population. Interestingly, the fraction of CD8(+) effector memory T cells was increased but this appeared to have little impact on the atherosclerosis development.In conclusion, Apoe(-/-)Tap1(-/-) mice develop atherosclerosis equal to Apoe(-/-) mice, indicating a minor role for CD8(+) T cells and TAP1-dependent antigen presentation in the disease process.

Show MeSH

Related in: MedlinePlus

CD11c+ cells and expression of CD80+, CD86+ and MHC class II+ on CD11c+ cells in spleen and MeLN.Histograms corresponding to the cell populations in the spleen from one representative mouse from each group (A). Gate boundaries were set by fluorescence minus one controls (solid grey). The fraction of CD11c+ cells (B) and CD11c+CD80+, CD11c+CD86+ and CD11c+MHCII+ cells in spleen (C) and MeLN (D) of Apoe−/− and Apoe−/− Tap1−/− mice. The cells were isolated from respective tissue, stained with fluorescent antibodies and analyzed by flow cytometry. Each dot in the figure represents one mouse. *P<0.05, **P<0.01.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3316507&req=5

pone-0033932-g004: CD11c+ cells and expression of CD80+, CD86+ and MHC class II+ on CD11c+ cells in spleen and MeLN.Histograms corresponding to the cell populations in the spleen from one representative mouse from each group (A). Gate boundaries were set by fluorescence minus one controls (solid grey). The fraction of CD11c+ cells (B) and CD11c+CD80+, CD11c+CD86+ and CD11c+MHCII+ cells in spleen (C) and MeLN (D) of Apoe−/− and Apoe−/− Tap1−/− mice. The cells were isolated from respective tissue, stained with fluorescent antibodies and analyzed by flow cytometry. Each dot in the figure represents one mouse. *P<0.05, **P<0.01.

Mentions: The T cell and dendritic cell (DC) populations of spleen and MeLN were analyzed to characterize the response to hypercholesterolemia systemically and in conjunction to lesions. While viable CD3+ T cells were less abundant in spleen of Apoe−/−Tap1−/− mice (figure 3A and 3B), there was no difference in MeLN compared to Apoe−/− mice (figure 3B). The fraction of CD3+CD4+ T cells was higher in Apoe−/−Tap1−/− mice and Tap1−/− mice compared to Apoe−/−mice in both spleen and MeLN (figure 3A and 3C and data not shown). While the increase in spleen was moderate, the CD3+CD4+ T cell compartment in MeLN was almost doubled (figure 3C), which may explain the difference in CD3+ T cells between the groups in spleen compared to the indifference between groups in MeLN (figure 3B). However, since the number of CD4+ T cells did not differ in MeLN (figure 3D) the relative rise in the CD4+ T cell population is likely a result of the diminished CD8+ T cell population. Interestingly, the number of CD4+ T cells in spleen increased in the Apoe−/−Tap1−/− mice (figure 3D). Since this population could mediate inflammation we analyzed the fraction of memory effector cells. There was no difference in CD4+CD44+CD62L− T cells in Apoe−/−Tap1−/− mice compared to Apoe−/−mice in MeLN or spleen (figure S1A). Surprisingly, the corresponding CD8+ population was approximately eight times larger in MeLN and spleen of Apoe−/−Tap1−/− mice compared to Apoe−/−mice (figure S1B). However, the CD8+CD44+CD62L+CD122+ regulatory T cell [19] population in the small CD8+ T cell population was also higher in Apoe−/−Tap1−/− mice (figure S2), which could compensate rise in effector cells. In contrast, within the CD4+ population the CD4+CD25+FoxP3+ regulatory T cell fraction was decreased in MeLN but not in spleen of Apoe−/−Tap1−/− mice given HFD for 8 weeks (14 weeks old at death) compared to equivalent Apoe−/− mice (figure S3). Since the major activation pathway of CD8+ T cells occur via DCs we analyzed abundance and activation of CD11c+ cells in spleen and MeLN of 26 weeks old mice. The fraction of CD11c+ cells in spleen, but not in MeLN, was lower in Apoe−/−Tap1−/− mice compared to Apoe−/−mice (figure 4B). Further, CD11c+ cells in both organs expressed lower levels of CD80, CD86 and a trend towards decreased MHC class II levels (figure 4A, 4C and 4D).


TAP1-deficiency does not alter atherosclerosis development in Apoe-/- mice.

Kolbus D, Ljungcrantz I, Söderberg I, Alm R, Björkbacka H, Nilsson J, Fredrikson GN - PLoS ONE (2012)

CD11c+ cells and expression of CD80+, CD86+ and MHC class II+ on CD11c+ cells in spleen and MeLN.Histograms corresponding to the cell populations in the spleen from one representative mouse from each group (A). Gate boundaries were set by fluorescence minus one controls (solid grey). The fraction of CD11c+ cells (B) and CD11c+CD80+, CD11c+CD86+ and CD11c+MHCII+ cells in spleen (C) and MeLN (D) of Apoe−/− and Apoe−/− Tap1−/− mice. The cells were isolated from respective tissue, stained with fluorescent antibodies and analyzed by flow cytometry. Each dot in the figure represents one mouse. *P<0.05, **P<0.01.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3316507&req=5

pone-0033932-g004: CD11c+ cells and expression of CD80+, CD86+ and MHC class II+ on CD11c+ cells in spleen and MeLN.Histograms corresponding to the cell populations in the spleen from one representative mouse from each group (A). Gate boundaries were set by fluorescence minus one controls (solid grey). The fraction of CD11c+ cells (B) and CD11c+CD80+, CD11c+CD86+ and CD11c+MHCII+ cells in spleen (C) and MeLN (D) of Apoe−/− and Apoe−/− Tap1−/− mice. The cells were isolated from respective tissue, stained with fluorescent antibodies and analyzed by flow cytometry. Each dot in the figure represents one mouse. *P<0.05, **P<0.01.
Mentions: The T cell and dendritic cell (DC) populations of spleen and MeLN were analyzed to characterize the response to hypercholesterolemia systemically and in conjunction to lesions. While viable CD3+ T cells were less abundant in spleen of Apoe−/−Tap1−/− mice (figure 3A and 3B), there was no difference in MeLN compared to Apoe−/− mice (figure 3B). The fraction of CD3+CD4+ T cells was higher in Apoe−/−Tap1−/− mice and Tap1−/− mice compared to Apoe−/−mice in both spleen and MeLN (figure 3A and 3C and data not shown). While the increase in spleen was moderate, the CD3+CD4+ T cell compartment in MeLN was almost doubled (figure 3C), which may explain the difference in CD3+ T cells between the groups in spleen compared to the indifference between groups in MeLN (figure 3B). However, since the number of CD4+ T cells did not differ in MeLN (figure 3D) the relative rise in the CD4+ T cell population is likely a result of the diminished CD8+ T cell population. Interestingly, the number of CD4+ T cells in spleen increased in the Apoe−/−Tap1−/− mice (figure 3D). Since this population could mediate inflammation we analyzed the fraction of memory effector cells. There was no difference in CD4+CD44+CD62L− T cells in Apoe−/−Tap1−/− mice compared to Apoe−/−mice in MeLN or spleen (figure S1A). Surprisingly, the corresponding CD8+ population was approximately eight times larger in MeLN and spleen of Apoe−/−Tap1−/− mice compared to Apoe−/−mice (figure S1B). However, the CD8+CD44+CD62L+CD122+ regulatory T cell [19] population in the small CD8+ T cell population was also higher in Apoe−/−Tap1−/− mice (figure S2), which could compensate rise in effector cells. In contrast, within the CD4+ population the CD4+CD25+FoxP3+ regulatory T cell fraction was decreased in MeLN but not in spleen of Apoe−/−Tap1−/− mice given HFD for 8 weeks (14 weeks old at death) compared to equivalent Apoe−/− mice (figure S3). Since the major activation pathway of CD8+ T cells occur via DCs we analyzed abundance and activation of CD11c+ cells in spleen and MeLN of 26 weeks old mice. The fraction of CD11c+ cells in spleen, but not in MeLN, was lower in Apoe−/−Tap1−/− mice compared to Apoe−/−mice (figure 4B). Further, CD11c+ cells in both organs expressed lower levels of CD80, CD86 and a trend towards decreased MHC class II levels (figure 4A, 4C and 4D).

Bottom Line: Antigen presenting cells (APC) have the ability to present both extra-cellular and intra-cellular antigens via MHC class I molecules to CD8(+) T cells.The cross presentation of extra-cellular antigens is reduced in mice with deficient Antigen Peptide Transporter 1 (TAP1)-dependent MHC class I antigen presentation, and these mice are characterized by a diminished CD8(+) T cell population.Interestingly, the fraction of CD8(+) effector memory T cells was increased but this appeared to have little impact on the atherosclerosis development.In conclusion, Apoe(-/-)Tap1(-/-) mice develop atherosclerosis equal to Apoe(-/-) mice, indicating a minor role for CD8(+) T cells and TAP1-dependent antigen presentation in the disease process.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Sciences, Skane University Hospital Malmö, Lund University, Malmö, Sweden.

ABSTRACT
Antigen presenting cells (APC) have the ability to present both extra-cellular and intra-cellular antigens via MHC class I molecules to CD8(+) T cells. The cross presentation of extra-cellular antigens is reduced in mice with deficient Antigen Peptide Transporter 1 (TAP1)-dependent MHC class I antigen presentation, and these mice are characterized by a diminished CD8(+) T cell population. We have recently reported an increased activation of CD8(+) T cells in hypercholesterolemic Apoe(-/-) mice. Therefore, this study included TAP1-deficient Apoe(-/-) mice (Apoe(-/-)Tap1(-/-)) to test the atherogenicity of CD8(+) T cells and TAP1-dependent cross presentation in a hypercholesterolemic environment. As expected the CD8(+) T cell numbers were low in Apoe(-/-)Tap1(-/-) mice in comparison to Apoe(-/-) mice, constituting ~1% of the lymphocyte population. In spite of this there were no differences in the extent of atherosclerosis as assessed by en face Oil Red O staining of the aorta and cross-sections of the aortic root between Apoe(-/-)Tap1(-/-) and Apoe(-/-) mice. Moreover, no differences were detected in lesion infiltration of macrophages or CD3(+) T cells in Apoe(-/-)Tap1(-/-) compared to Apoe(-/-) mice. The CD3(+)CD4(+) T cell fraction was increased in Apoe(-/-)Tap1(-/-) mice, suggesting a compensation for the decreased CD8(+) T cell population. Interestingly, the fraction of CD8(+) effector memory T cells was increased but this appeared to have little impact on the atherosclerosis development.In conclusion, Apoe(-/-)Tap1(-/-) mice develop atherosclerosis equal to Apoe(-/-) mice, indicating a minor role for CD8(+) T cells and TAP1-dependent antigen presentation in the disease process.

Show MeSH
Related in: MedlinePlus