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Effective elicitation of human effector CD8+ T Cells in HLA-B*51:01 transgenic humanized mice after infection with HIV-1.

Sato Y, Nagata S, Takiguchi M - PLoS ONE (2012)

Bottom Line: However, it is well known that human CD8(+) T cells cannot differentiate into effector cells in immunodeficient mice transplanted with only human CD34(+) hematopoietic stem cells (HSCs), because human T cells are not educated by HLA in the mouse thymus.There were no differences in the frequency of late effector memory and effector subsets (CD27(low)CD28(-)CD45RA(+/-)CCR7(-) and CD27(-)CD28(-)CD45RA(+/-)CCR7(-), respectively) among human CD8(+) T cells and in that of human CD8(+) T cells expressing CX3CR1 and/or CXCR1 between hNOK/B51Tg and hNOK mice.These results suggest that hNOK/B51Tg mice had CD8(+) T cells that were capable of differentiating into effector T cells after viral antigen stimulation and had a greater ability to elicit effector CD8(+) T cells than hNOK ones.

View Article: PubMed Central - PubMed

Affiliation: Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto, Japan.

ABSTRACT
Humanized mice are expected to be useful as small animal models for in vivo studies on the pathogenesis of infectious diseases. However, it is well known that human CD8(+) T cells cannot differentiate into effector cells in immunodeficient mice transplanted with only human CD34(+) hematopoietic stem cells (HSCs), because human T cells are not educated by HLA in the mouse thymus. We here established HLA-B*51:01 transgenic humanized mice by transplanting human CD34(+) HSCs into HLA-B*51:01 transgenic NOD/SCID/Jak3(-/-) mice (hNOK/B51Tg mice) and investigated whether human effector CD8(+) T cells would be elicited in the mice or in those infected with HIV-1 NL4-3. There were no differences in the frequency of late effector memory and effector subsets (CD27(low)CD28(-)CD45RA(+/-)CCR7(-) and CD27(-)CD28(-)CD45RA(+/-)CCR7(-), respectively) among human CD8(+) T cells and in that of human CD8(+) T cells expressing CX3CR1 and/or CXCR1 between hNOK/B51Tg and hNOK mice. In contrast, the frequency of late effector memory and effector CD8(+) T cell subsets and of those expressing CX3CR1 and/or CXCR1 was significantly higher in HIV-1-infected hNOK/B51Tg mice than in uninfected ones, whereas there was no difference in that of these subsets between HIV-1-infected and uninfected hNOK mice. These results suggest that hNOK/B51Tg mice had CD8(+) T cells that were capable of differentiating into effector T cells after viral antigen stimulation and had a greater ability to elicit effector CD8(+) T cells than hNOK ones.

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Expression of CX3CR1 and CXCR1 chemokine receptors on human CD8+ T cells from HIV-1-infected and uninfected hNOK/B51Tg mice and from HIV-1-infected and uninfected hNOK mice.Human CD8+ T cells from the spleens of HIV-1-infected hNOK/B51Tg and hNOK mice at 6 weeks post-infection as well as those from uninfected ones at 20 weeks after the transplantation of CD34+ HSCs were analyzed for the expression of CX3CR1 and CXCR1 molecules. (A) Representative results on CX3CR1 and CXCR1 co-expression on human CD8+ T cells from an HIV-1-infected hNOK/B51Tg mouse and from an uninfected one (upper data) as well as from an HIV-1-infected hNOK mouse and an uninfected one (lower data) are shown. (B) Summarized results on the frequency of human CD8+ T cells expressing CX3CR1 and/or CXCR1 from HIV-1-infected hNOK/B51Tg (n = 7, black circles) and uninfected (n = 6, white circles) mice as well as that for HIV-1-infected hNOK (n = 8, black triangles) and uninfected mice (n = 6, white triangles). Each symbol represents an individual mouse; and the mean value is shown as a horizontal solid line. Asterisks indicate statistically significant differences (*p<0.05).
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pone-0042776-g004: Expression of CX3CR1 and CXCR1 chemokine receptors on human CD8+ T cells from HIV-1-infected and uninfected hNOK/B51Tg mice and from HIV-1-infected and uninfected hNOK mice.Human CD8+ T cells from the spleens of HIV-1-infected hNOK/B51Tg and hNOK mice at 6 weeks post-infection as well as those from uninfected ones at 20 weeks after the transplantation of CD34+ HSCs were analyzed for the expression of CX3CR1 and CXCR1 molecules. (A) Representative results on CX3CR1 and CXCR1 co-expression on human CD8+ T cells from an HIV-1-infected hNOK/B51Tg mouse and from an uninfected one (upper data) as well as from an HIV-1-infected hNOK mouse and an uninfected one (lower data) are shown. (B) Summarized results on the frequency of human CD8+ T cells expressing CX3CR1 and/or CXCR1 from HIV-1-infected hNOK/B51Tg (n = 7, black circles) and uninfected (n = 6, white circles) mice as well as that for HIV-1-infected hNOK (n = 8, black triangles) and uninfected mice (n = 6, white triangles). Each symbol represents an individual mouse; and the mean value is shown as a horizontal solid line. Asterisks indicate statistically significant differences (*p<0.05).

Mentions: Previous studies showed that CXCR1+ cells are predominantly found among human CD8+ T cells having effector function and that the expression of CXCR1 is positively correlated with that of perforin [34], [35]. An additional study revealed that CX3CR1 expression is closely associated with the development of effector functions in human CD8+ T cells and that CX3CR1-expressing CD8+ T cells represent a group of fully differentiated effector CD8+ T cells [36]–[38]. Based on the expression pattern of these molecules, we analyzed the frequency of human CD8+ T cells expressing CX3CR1 and/or CXCR1 from the spleens of HIV-1-infected and uninfected hNOK/B51Tg mice and of HIV-1-infected and uninfected hNOK mice at 6 weeks post-infection. Representative results from an HIV-1-infected hNOK/B51Tg mouse and an uninfected one as well as those from an HIV-1-infected hNOK mouse and an uninfected one are shown in Figure 4A. Only 3 subsets (CX3CR1+CXCR1+, CX3CR1+CXCR1−, and CX3CR1−CXCR1−) were detected in these mice. Summaries of the results from 7 HIV-1-infected and 6 uninfected hNOK/B51Tg mice as well as from 8 HIV-1-infected hNOK and 6 uninfected mice are shown in Figure 4B. The frequency of human CD8+ T cells expressing CX3CR1 and/or CXCR1 for HIV-1-infected hNOK/B51Tg mice was significantly higher than that for the uninfected ones, whereas the frequency of human CD8+ T cells expressing CX3CR1 and/or CXCR1 for the HIV-1-infected hNOK mice was not significantly higher than that for the uninfected ones. In addition, the frequency of human CD8+ T cells expressing both CX3CR1 and CXCR1 for the HIV-1-infected hNOK/B51Tg mice was significantly higher than that for the HIV-1-infected hNOK mice. These results support the idea that human CD8+ T cells having effector function were induced by the HIV-1 infection in hNOK/B51Tg mice.


Effective elicitation of human effector CD8+ T Cells in HLA-B*51:01 transgenic humanized mice after infection with HIV-1.

Sato Y, Nagata S, Takiguchi M - PLoS ONE (2012)

Expression of CX3CR1 and CXCR1 chemokine receptors on human CD8+ T cells from HIV-1-infected and uninfected hNOK/B51Tg mice and from HIV-1-infected and uninfected hNOK mice.Human CD8+ T cells from the spleens of HIV-1-infected hNOK/B51Tg and hNOK mice at 6 weeks post-infection as well as those from uninfected ones at 20 weeks after the transplantation of CD34+ HSCs were analyzed for the expression of CX3CR1 and CXCR1 molecules. (A) Representative results on CX3CR1 and CXCR1 co-expression on human CD8+ T cells from an HIV-1-infected hNOK/B51Tg mouse and from an uninfected one (upper data) as well as from an HIV-1-infected hNOK mouse and an uninfected one (lower data) are shown. (B) Summarized results on the frequency of human CD8+ T cells expressing CX3CR1 and/or CXCR1 from HIV-1-infected hNOK/B51Tg (n = 7, black circles) and uninfected (n = 6, white circles) mice as well as that for HIV-1-infected hNOK (n = 8, black triangles) and uninfected mice (n = 6, white triangles). Each symbol represents an individual mouse; and the mean value is shown as a horizontal solid line. Asterisks indicate statistically significant differences (*p<0.05).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3412802&req=5

pone-0042776-g004: Expression of CX3CR1 and CXCR1 chemokine receptors on human CD8+ T cells from HIV-1-infected and uninfected hNOK/B51Tg mice and from HIV-1-infected and uninfected hNOK mice.Human CD8+ T cells from the spleens of HIV-1-infected hNOK/B51Tg and hNOK mice at 6 weeks post-infection as well as those from uninfected ones at 20 weeks after the transplantation of CD34+ HSCs were analyzed for the expression of CX3CR1 and CXCR1 molecules. (A) Representative results on CX3CR1 and CXCR1 co-expression on human CD8+ T cells from an HIV-1-infected hNOK/B51Tg mouse and from an uninfected one (upper data) as well as from an HIV-1-infected hNOK mouse and an uninfected one (lower data) are shown. (B) Summarized results on the frequency of human CD8+ T cells expressing CX3CR1 and/or CXCR1 from HIV-1-infected hNOK/B51Tg (n = 7, black circles) and uninfected (n = 6, white circles) mice as well as that for HIV-1-infected hNOK (n = 8, black triangles) and uninfected mice (n = 6, white triangles). Each symbol represents an individual mouse; and the mean value is shown as a horizontal solid line. Asterisks indicate statistically significant differences (*p<0.05).
Mentions: Previous studies showed that CXCR1+ cells are predominantly found among human CD8+ T cells having effector function and that the expression of CXCR1 is positively correlated with that of perforin [34], [35]. An additional study revealed that CX3CR1 expression is closely associated with the development of effector functions in human CD8+ T cells and that CX3CR1-expressing CD8+ T cells represent a group of fully differentiated effector CD8+ T cells [36]–[38]. Based on the expression pattern of these molecules, we analyzed the frequency of human CD8+ T cells expressing CX3CR1 and/or CXCR1 from the spleens of HIV-1-infected and uninfected hNOK/B51Tg mice and of HIV-1-infected and uninfected hNOK mice at 6 weeks post-infection. Representative results from an HIV-1-infected hNOK/B51Tg mouse and an uninfected one as well as those from an HIV-1-infected hNOK mouse and an uninfected one are shown in Figure 4A. Only 3 subsets (CX3CR1+CXCR1+, CX3CR1+CXCR1−, and CX3CR1−CXCR1−) were detected in these mice. Summaries of the results from 7 HIV-1-infected and 6 uninfected hNOK/B51Tg mice as well as from 8 HIV-1-infected hNOK and 6 uninfected mice are shown in Figure 4B. The frequency of human CD8+ T cells expressing CX3CR1 and/or CXCR1 for HIV-1-infected hNOK/B51Tg mice was significantly higher than that for the uninfected ones, whereas the frequency of human CD8+ T cells expressing CX3CR1 and/or CXCR1 for the HIV-1-infected hNOK mice was not significantly higher than that for the uninfected ones. In addition, the frequency of human CD8+ T cells expressing both CX3CR1 and CXCR1 for the HIV-1-infected hNOK/B51Tg mice was significantly higher than that for the HIV-1-infected hNOK mice. These results support the idea that human CD8+ T cells having effector function were induced by the HIV-1 infection in hNOK/B51Tg mice.

Bottom Line: However, it is well known that human CD8(+) T cells cannot differentiate into effector cells in immunodeficient mice transplanted with only human CD34(+) hematopoietic stem cells (HSCs), because human T cells are not educated by HLA in the mouse thymus.There were no differences in the frequency of late effector memory and effector subsets (CD27(low)CD28(-)CD45RA(+/-)CCR7(-) and CD27(-)CD28(-)CD45RA(+/-)CCR7(-), respectively) among human CD8(+) T cells and in that of human CD8(+) T cells expressing CX3CR1 and/or CXCR1 between hNOK/B51Tg and hNOK mice.These results suggest that hNOK/B51Tg mice had CD8(+) T cells that were capable of differentiating into effector T cells after viral antigen stimulation and had a greater ability to elicit effector CD8(+) T cells than hNOK ones.

View Article: PubMed Central - PubMed

Affiliation: Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto, Japan.

ABSTRACT
Humanized mice are expected to be useful as small animal models for in vivo studies on the pathogenesis of infectious diseases. However, it is well known that human CD8(+) T cells cannot differentiate into effector cells in immunodeficient mice transplanted with only human CD34(+) hematopoietic stem cells (HSCs), because human T cells are not educated by HLA in the mouse thymus. We here established HLA-B*51:01 transgenic humanized mice by transplanting human CD34(+) HSCs into HLA-B*51:01 transgenic NOD/SCID/Jak3(-/-) mice (hNOK/B51Tg mice) and investigated whether human effector CD8(+) T cells would be elicited in the mice or in those infected with HIV-1 NL4-3. There were no differences in the frequency of late effector memory and effector subsets (CD27(low)CD28(-)CD45RA(+/-)CCR7(-) and CD27(-)CD28(-)CD45RA(+/-)CCR7(-), respectively) among human CD8(+) T cells and in that of human CD8(+) T cells expressing CX3CR1 and/or CXCR1 between hNOK/B51Tg and hNOK mice. In contrast, the frequency of late effector memory and effector CD8(+) T cell subsets and of those expressing CX3CR1 and/or CXCR1 was significantly higher in HIV-1-infected hNOK/B51Tg mice than in uninfected ones, whereas there was no difference in that of these subsets between HIV-1-infected and uninfected hNOK mice. These results suggest that hNOK/B51Tg mice had CD8(+) T cells that were capable of differentiating into effector T cells after viral antigen stimulation and had a greater ability to elicit effector CD8(+) T cells than hNOK ones.

Show MeSH
Related in: MedlinePlus