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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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Detection and phenotypic analysis of endogenous HTLV-I Tax11-19 peptide–HLA-A*201 complexes on T cells from HAM/TSP patients. (A) Detection of naturally processed endogenous HTLV-I Tax11-19 peptide–HLA-A*201 complexes on T cells from a HAM/TSP patient. Representative histograms of the expression of Tax11-19 peptide–HLA-A*201 complexes on CD4+ and CD8+ T cells from a HAM/TSP patient before and after 24 h of culture. Percentage of positive staining for TaxA2-Ab is shown in the top right. (B) Phenotypic characterization of HTLV-I Tax11-19 peptide–HLA-A*201–expressing CD4+ T cells from HAM/TSP patients. 24-h cultured CD4+ T cells of HAM/TSP patients were stained by anti-CD4 Abs in combination with anti-CD25, anti-CD27, anti-CD45RO, or anti-CD45RA Abs. Representative histograms of Tax11-19 peptide–HLA-A*201 expression on each population are presented.
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fig2: Detection and phenotypic analysis of endogenous HTLV-I Tax11-19 peptide–HLA-A*201 complexes on T cells from HAM/TSP patients. (A) Detection of naturally processed endogenous HTLV-I Tax11-19 peptide–HLA-A*201 complexes on T cells from a HAM/TSP patient. Representative histograms of the expression of Tax11-19 peptide–HLA-A*201 complexes on CD4+ and CD8+ T cells from a HAM/TSP patient before and after 24 h of culture. Percentage of positive staining for TaxA2-Ab is shown in the top right. (B) Phenotypic characterization of HTLV-I Tax11-19 peptide–HLA-A*201–expressing CD4+ T cells from HAM/TSP patients. 24-h cultured CD4+ T cells of HAM/TSP patients were stained by anti-CD4 Abs in combination with anti-CD25, anti-CD27, anti-CD45RO, or anti-CD45RA Abs. Representative histograms of Tax11-19 peptide–HLA-A*201 expression on each population are presented.

Mentions: Using this TaxA2-Ab, the expression of Tax11-19 peptide–HLA-A*201 complexes was analyzed on T cells from HAM/TSP patients. It has been reported that HTLV-I infects both CD4+ and CD8+ T cells (20, 22). Although HTLV-I antigen expression ex vivo is negligible, infected cells can start to express HTLV-I antigen after short-term culture (32). Therefore, CD4+ and CD8+ T cells were separated using MACS beads and the expression of Tax11-19 peptide–HLA-A*201 complexes on each T cell subset before and after culture was investigated using the TaxA2-Ab. Before culture, the Tax11-19 peptide–HLA-A*201 complexes could not be detected both on ex vivo CD4+ and CD8+ T cells (Fig. 2 A). However, after 24 h of culture, the expression of Tax11-19 peptide–HLA-A*201 complexes was demonstrated on CD4+ T cells, but not on CD8+ T cells (Fig. 2 A). These results indicate that the peptide-specific, MHC-restricted Fab Abs are capable of detecting the specific peptide–HLA complexes after natural endogenous intracellular antigen processing as previously reported (29), and in HAM/TSP patients CD4+ T cells present more Tax11-19 peptide–HLA-A*201 complexes than CD8+ T 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)

Detection and phenotypic analysis of endogenous HTLV-I Tax11-19 peptide–HLA-A*201 complexes on T cells from HAM/TSP patients. (A) Detection of naturally processed endogenous HTLV-I Tax11-19 peptide–HLA-A*201 complexes on T cells from a HAM/TSP patient. Representative histograms of the expression of Tax11-19 peptide–HLA-A*201 complexes on CD4+ and CD8+ T cells from a HAM/TSP patient before and after 24 h of culture. Percentage of positive staining for TaxA2-Ab is shown in the top right. (B) Phenotypic characterization of HTLV-I Tax11-19 peptide–HLA-A*201–expressing CD4+ T cells from HAM/TSP patients. 24-h cultured CD4+ T cells of HAM/TSP patients were stained by anti-CD4 Abs in combination with anti-CD25, anti-CD27, anti-CD45RO, or anti-CD45RA Abs. Representative histograms of Tax11-19 peptide–HLA-A*201 expression on each population are presented.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2211812&req=5

fig2: Detection and phenotypic analysis of endogenous HTLV-I Tax11-19 peptide–HLA-A*201 complexes on T cells from HAM/TSP patients. (A) Detection of naturally processed endogenous HTLV-I Tax11-19 peptide–HLA-A*201 complexes on T cells from a HAM/TSP patient. Representative histograms of the expression of Tax11-19 peptide–HLA-A*201 complexes on CD4+ and CD8+ T cells from a HAM/TSP patient before and after 24 h of culture. Percentage of positive staining for TaxA2-Ab is shown in the top right. (B) Phenotypic characterization of HTLV-I Tax11-19 peptide–HLA-A*201–expressing CD4+ T cells from HAM/TSP patients. 24-h cultured CD4+ T cells of HAM/TSP patients were stained by anti-CD4 Abs in combination with anti-CD25, anti-CD27, anti-CD45RO, or anti-CD45RA Abs. Representative histograms of Tax11-19 peptide–HLA-A*201 expression on each population are presented.
Mentions: Using this TaxA2-Ab, the expression of Tax11-19 peptide–HLA-A*201 complexes was analyzed on T cells from HAM/TSP patients. It has been reported that HTLV-I infects both CD4+ and CD8+ T cells (20, 22). Although HTLV-I antigen expression ex vivo is negligible, infected cells can start to express HTLV-I antigen after short-term culture (32). Therefore, CD4+ and CD8+ T cells were separated using MACS beads and the expression of Tax11-19 peptide–HLA-A*201 complexes on each T cell subset before and after culture was investigated using the TaxA2-Ab. Before culture, the Tax11-19 peptide–HLA-A*201 complexes could not be detected both on ex vivo CD4+ and CD8+ T cells (Fig. 2 A). However, after 24 h of culture, the expression of Tax11-19 peptide–HLA-A*201 complexes was demonstrated on CD4+ T cells, but not on CD8+ T cells (Fig. 2 A). These results indicate that the peptide-specific, MHC-restricted Fab Abs are capable of detecting the specific peptide–HLA complexes after natural endogenous intracellular antigen processing as previously reported (29), and in HAM/TSP patients CD4+ T cells present more Tax11-19 peptide–HLA-A*201 complexes than CD8+ T 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