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Increased expression of human T lymphocyte virus type I (HTLV-I) Tax11-19 peptide-human histocompatibility leukocyte antigen A*201 complexes on CD4+ CD25+ T Cells detected by peptide-specific, major histocompatibility complex-restricted antibodies in patients with HTLV-I-associated neurologic disease.

Yamano Y, Cohen CJ, Takenouchi N, Yao K, Tomaru U, Li HC, Reiter Y, Jacobson S - J. Exp. Med. (2004)

Bottom Line: Human T lymphocyte virus type I (HTLV-I)-associated chronic inflammatory neurological disease (HTLV-I-associated myelopathy/tropical spastic paraparesis [HAM/TSP]) is suggested to be an immunopathologically mediated disorder characterized by large numbers of HTLV-I Tax-specific CD8+ T cells.However, until now, it has not been possible to identify and/or quantify these peptide-HLA complexes.These results indicate that the increased detection and visualization of peptide-HLA complexes in HAM/TSP CD4+ CD25+ T cell subsets that are shown to stimulate and expand HTLV-I Tax-specific CD8+ T cells may play an important role in the pathogenesis of HTLV-I-associated neurological disease.

View Article: PubMed Central - PubMed

Affiliation: Viral Immunology Section, Neuroimmunology Branch, National Institutes of Health, National Institute of Neurological Disorders and Strokes, Building 10, Room 5B-16, Bethesda, MD 20892, USA.

ABSTRACT
Human T lymphocyte virus type I (HTLV-I)-associated chronic inflammatory neurological disease (HTLV-I-associated myelopathy/tropical spastic paraparesis [HAM/TSP]) is suggested to be an immunopathologically mediated disorder characterized by large numbers of HTLV-I Tax-specific CD8+ T cells. The frequency of these cells in the peripheral blood and cerebrospinal fluid is proportional to the amount of HTLV-I proviral load and the levels of HTLV-I tax mRNA expression. As the stimulus for these virus-specific T cells are immunodominant peptide-human histocompatibility leukocyte antigen (HLA) complexes expressed on antigen-presenting cells, it was of interest to determine which cells express these complexes and at what frequency. However, until now, it has not been possible to identify and/or quantify these peptide-HLA complexes. Using a recently developed antibody that specifically recognizes Tax11-19 peptide-HLA-A*201 complexes, the level of Tax11-19-HLA-A*201 expression on T cells was demonstrated to be increased in HAM/TSP and correlated with HTLV-I proviral DNA load, HTLV-I tax mRNA load, and HTLV-I Tax-specific CD8+ T cell frequencies. Furthermore, CD4+ CD25+ T cells were demonstrated to be the major reservoir of HTLV-I provirus as well as Tax11-19 peptide-HLA-A*201 complexes. These results indicate that the increased detection and visualization of peptide-HLA complexes in HAM/TSP CD4+ CD25+ T cell subsets that are shown to stimulate and expand HTLV-I Tax-specific CD8+ T cells may play an important role in the pathogenesis of HTLV-I-associated neurological disease.

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Proliferation of HTLV-I Tax–specific CD8+ T cells are stimulated by CD4+ CD25+ T cells in HAM/TSP patients. (A) Proliferation of CD8+ T cells stimulated by autologous CD4+ CD25+ T cells in HAM/TSP patients. Purified CD4+ CD25+ and CD4+ CD25− T cells from three HAM/TSP patients (HAM 4–6; HTLV-I Tax11-19–HLA-A*201 tetramer–specific T cell frequency in total CD8 was 13.24, 5.70, and 1.78%, respectively) were cultured for 24 h and irradiated. Autologous CD8+ T cells were then incubated with the CD4+ CD25+ or CD4+ CD25− T cells for 4 d and proliferation of CD8+ T cells was assessed by the incorporation of [3H]thymidine (1 μCi/well) during the last 16 h of culture. In these experiments, background counts in the wells containing APCs were <300 cpm. (B) Proliferation of CD8+ T cells stimulated by autologous CD4+ CD25+ T cells in a HAM/TSP patient. Histograms of intracellular Ki-67 staining in CD8+ T cells when stimulated by irradiated, cultured, autologous CD4+ CD25+ or CD4+ CD25− T cells are presented. Percentage of positive staining for Ki-67 is shown in the center. (C) Proliferation of HTLV-I Tax11-19–specific T cells stimulated by autologous CD4+ CD25+ T cells in a HAM/TSP patient. Dot plots of intracellular Ki-67 staining in CD8+ T cells, Tax11-19–HLA-A*201 tetramer+ CD8+ T cells, and CMV pp65–HLA-A*201 tetramer+ CD8+ T cells when stimulated by irradiated, cultured, autologous CD4+ CD25+ or CD4+ CD25− T cells are presented. Percentage of positive staining for Ki-67 is shown in the top right.
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fig4: Proliferation of HTLV-I Tax–specific CD8+ T cells are stimulated by CD4+ CD25+ T cells in HAM/TSP patients. (A) Proliferation of CD8+ T cells stimulated by autologous CD4+ CD25+ T cells in HAM/TSP patients. Purified CD4+ CD25+ and CD4+ CD25− T cells from three HAM/TSP patients (HAM 4–6; HTLV-I Tax11-19–HLA-A*201 tetramer–specific T cell frequency in total CD8 was 13.24, 5.70, and 1.78%, respectively) were cultured for 24 h and irradiated. Autologous CD8+ T cells were then incubated with the CD4+ CD25+ or CD4+ CD25− T cells for 4 d and proliferation of CD8+ T cells was assessed by the incorporation of [3H]thymidine (1 μCi/well) during the last 16 h of culture. In these experiments, background counts in the wells containing APCs were <300 cpm. (B) Proliferation of CD8+ T cells stimulated by autologous CD4+ CD25+ T cells in a HAM/TSP patient. Histograms of intracellular Ki-67 staining in CD8+ T cells when stimulated by irradiated, cultured, autologous CD4+ CD25+ or CD4+ CD25− T cells are presented. Percentage of positive staining for Ki-67 is shown in the center. (C) Proliferation of HTLV-I Tax11-19–specific T cells stimulated by autologous CD4+ CD25+ T cells in a HAM/TSP patient. Dot plots of intracellular Ki-67 staining in CD8+ T cells, Tax11-19–HLA-A*201 tetramer+ CD8+ T cells, and CMV pp65–HLA-A*201 tetramer+ CD8+ T cells when stimulated by irradiated, cultured, autologous CD4+ CD25+ or CD4+ CD25− T cells are presented. Percentage of positive staining for Ki-67 is shown in the top right.

Mentions: Having observed that CD4+ CD25+ T cells are preferentially infected with HTLV-I and express Tax11-19 peptide–HLA-A*201 complexes, we tested whether these cells can stimulate the proliferation of autologous CD8+ T cells (and more specifically, HTLV-I–specific CD8+ T cells) in HAM/TSP patients. Peripheral blood T cells from three HAM/TSP patients were separated into CD4+ CD25+ and CD4+ CD25− cells and cultured for 24 h. After culture, both populations were irradiated. Autologous CD8+ T cells were then added at a 1:1 ratio where proliferation of CD8+ T cells was analyzed after 4 d of culture. As shown in Fig. 4 A, CD4+ CD25+ T cells from HAM/TSP patients preferentially stimulated the proliferation of autologous CD8+ cells.


Increased expression of human T lymphocyte virus type I (HTLV-I) Tax11-19 peptide-human histocompatibility leukocyte antigen A*201 complexes on CD4+ CD25+ T Cells detected by peptide-specific, major histocompatibility complex-restricted antibodies in patients with HTLV-I-associated neurologic disease.

Yamano Y, Cohen CJ, Takenouchi N, Yao K, Tomaru U, Li HC, Reiter Y, Jacobson S - J. Exp. Med. (2004)

Proliferation of HTLV-I Tax–specific CD8+ T cells are stimulated by CD4+ CD25+ T cells in HAM/TSP patients. (A) Proliferation of CD8+ T cells stimulated by autologous CD4+ CD25+ T cells in HAM/TSP patients. Purified CD4+ CD25+ and CD4+ CD25− T cells from three HAM/TSP patients (HAM 4–6; HTLV-I Tax11-19–HLA-A*201 tetramer–specific T cell frequency in total CD8 was 13.24, 5.70, and 1.78%, respectively) were cultured for 24 h and irradiated. Autologous CD8+ T cells were then incubated with the CD4+ CD25+ or CD4+ CD25− T cells for 4 d and proliferation of CD8+ T cells was assessed by the incorporation of [3H]thymidine (1 μCi/well) during the last 16 h of culture. In these experiments, background counts in the wells containing APCs were <300 cpm. (B) Proliferation of CD8+ T cells stimulated by autologous CD4+ CD25+ T cells in a HAM/TSP patient. Histograms of intracellular Ki-67 staining in CD8+ T cells when stimulated by irradiated, cultured, autologous CD4+ CD25+ or CD4+ CD25− T cells are presented. Percentage of positive staining for Ki-67 is shown in the center. (C) Proliferation of HTLV-I Tax11-19–specific T cells stimulated by autologous CD4+ CD25+ T cells in a HAM/TSP patient. Dot plots of intracellular Ki-67 staining in CD8+ T cells, Tax11-19–HLA-A*201 tetramer+ CD8+ T cells, and CMV pp65–HLA-A*201 tetramer+ CD8+ T cells when stimulated by irradiated, cultured, autologous CD4+ CD25+ or CD4+ CD25− T cells are presented. Percentage of positive staining for Ki-67 is shown in the top right.
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Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211812&req=5

fig4: Proliferation of HTLV-I Tax–specific CD8+ T cells are stimulated by CD4+ CD25+ T cells in HAM/TSP patients. (A) Proliferation of CD8+ T cells stimulated by autologous CD4+ CD25+ T cells in HAM/TSP patients. Purified CD4+ CD25+ and CD4+ CD25− T cells from three HAM/TSP patients (HAM 4–6; HTLV-I Tax11-19–HLA-A*201 tetramer–specific T cell frequency in total CD8 was 13.24, 5.70, and 1.78%, respectively) were cultured for 24 h and irradiated. Autologous CD8+ T cells were then incubated with the CD4+ CD25+ or CD4+ CD25− T cells for 4 d and proliferation of CD8+ T cells was assessed by the incorporation of [3H]thymidine (1 μCi/well) during the last 16 h of culture. In these experiments, background counts in the wells containing APCs were <300 cpm. (B) Proliferation of CD8+ T cells stimulated by autologous CD4+ CD25+ T cells in a HAM/TSP patient. Histograms of intracellular Ki-67 staining in CD8+ T cells when stimulated by irradiated, cultured, autologous CD4+ CD25+ or CD4+ CD25− T cells are presented. Percentage of positive staining for Ki-67 is shown in the center. (C) Proliferation of HTLV-I Tax11-19–specific T cells stimulated by autologous CD4+ CD25+ T cells in a HAM/TSP patient. Dot plots of intracellular Ki-67 staining in CD8+ T cells, Tax11-19–HLA-A*201 tetramer+ CD8+ T cells, and CMV pp65–HLA-A*201 tetramer+ CD8+ T cells when stimulated by irradiated, cultured, autologous CD4+ CD25+ or CD4+ CD25− T cells are presented. Percentage of positive staining for Ki-67 is shown in the top right.
Mentions: Having observed that CD4+ CD25+ T cells are preferentially infected with HTLV-I and express Tax11-19 peptide–HLA-A*201 complexes, we tested whether these cells can stimulate the proliferation of autologous CD8+ T cells (and more specifically, HTLV-I–specific CD8+ T cells) in HAM/TSP patients. Peripheral blood T cells from three HAM/TSP patients were separated into CD4+ CD25+ and CD4+ CD25− cells and cultured for 24 h. After culture, both populations were irradiated. Autologous CD8+ T cells were then added at a 1:1 ratio where proliferation of CD8+ T cells was analyzed after 4 d of culture. As shown in Fig. 4 A, CD4+ CD25+ T cells from HAM/TSP patients preferentially stimulated the proliferation of autologous CD8+ cells.

Bottom Line: Human T lymphocyte virus type I (HTLV-I)-associated chronic inflammatory neurological disease (HTLV-I-associated myelopathy/tropical spastic paraparesis [HAM/TSP]) is suggested to be an immunopathologically mediated disorder characterized by large numbers of HTLV-I Tax-specific CD8+ T cells.However, until now, it has not been possible to identify and/or quantify these peptide-HLA complexes.These results indicate that the increased detection and visualization of peptide-HLA complexes in HAM/TSP CD4+ CD25+ T cell subsets that are shown to stimulate and expand HTLV-I Tax-specific CD8+ T cells may play an important role in the pathogenesis of HTLV-I-associated neurological disease.

View Article: PubMed Central - PubMed

Affiliation: Viral Immunology Section, Neuroimmunology Branch, National Institutes of Health, National Institute of Neurological Disorders and Strokes, Building 10, Room 5B-16, Bethesda, MD 20892, USA.

ABSTRACT
Human T lymphocyte virus type I (HTLV-I)-associated chronic inflammatory neurological disease (HTLV-I-associated myelopathy/tropical spastic paraparesis [HAM/TSP]) is suggested to be an immunopathologically mediated disorder characterized by large numbers of HTLV-I Tax-specific CD8+ T cells. The frequency of these cells in the peripheral blood and cerebrospinal fluid is proportional to the amount of HTLV-I proviral load and the levels of HTLV-I tax mRNA expression. As the stimulus for these virus-specific T cells are immunodominant peptide-human histocompatibility leukocyte antigen (HLA) complexes expressed on antigen-presenting cells, it was of interest to determine which cells express these complexes and at what frequency. However, until now, it has not been possible to identify and/or quantify these peptide-HLA complexes. Using a recently developed antibody that specifically recognizes Tax11-19 peptide-HLA-A*201 complexes, the level of Tax11-19-HLA-A*201 expression on T cells was demonstrated to be increased in HAM/TSP and correlated with HTLV-I proviral DNA load, HTLV-I tax mRNA load, and HTLV-I Tax-specific CD8+ T cell frequencies. Furthermore, CD4+ CD25+ T cells were demonstrated to be the major reservoir of HTLV-I provirus as well as Tax11-19 peptide-HLA-A*201 complexes. These results indicate that the increased detection and visualization of peptide-HLA complexes in HAM/TSP CD4+ CD25+ T cell subsets that are shown to stimulate and expand HTLV-I Tax-specific CD8+ T cells may play an important role in the pathogenesis of HTLV-I-associated neurological disease.

Show MeSH
Related in: MedlinePlus