Limits...
Mutant Huntingtin Does Not Affect the Intrinsic Phenotype of Human Huntington's Disease T Lymphocytes.

Miller JR, Träger U, Andre R, Tabrizi SJ - PLoS ONE (2015)

Bottom Line: However, it is not clear whether or to what extent the adaptive immune system is also involved.The transcriptional profile of T lymphocytes also does not appear to be significantly affected, suggesting that peripheral immune dysfunction in Huntington's disease is likely to be mediated primarily by the innate rather than the adaptive immune system.Finally, this study suggests that the potential use of novel therapeutics aimed at modulating the Huntington's disease innate immune system should not be extended to include the adaptive immune system.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.

ABSTRACT
Huntington's disease is a fatal neurodegenerative condition caused by a CAG repeat expansion in the huntingtin gene. The peripheral innate immune system is dysregulated in Huntington's disease and may contribute to its pathogenesis. However, it is not clear whether or to what extent the adaptive immune system is also involved. Here, we carry out the first comprehensive investigation of human ex vivo T lymphocytes in Huntington's disease, focusing on the frequency of a range of T lymphocyte subsets, as well as analysis of proliferation, cytokine production and gene transcription. In contrast to the innate immune system, the intrinsic phenotype of T lymphocytes does not appear to be affected by the presence of mutant huntingtin, with Huntington's disease T lymphocytes exhibiting no significant functional differences compared to control cells. The transcriptional profile of T lymphocytes also does not appear to be significantly affected, suggesting that peripheral immune dysfunction in Huntington's disease is likely to be mediated primarily by the innate rather than the adaptive immune system. This study increases our understanding of the effects of Huntington's disease on peripheral tissues, while further demonstrating the differential effects of the mutant protein on different but related cell types. Finally, this study suggests that the potential use of novel therapeutics aimed at modulating the Huntington's disease innate immune system should not be extended to include the adaptive immune system.

No MeSH data available.


Related in: MedlinePlus

The percentage of proliferating CD3+ T lymphocytes is not affected in HD compared to control.PBMCs were stained with CFSE and the percentage of CD3+ T lymphocytes from the initial culture which divided (A) in the absence of stimulation (B) with 5 μg/ml anti-CD3 and 2 μg/ml anti-CD28 antibody stimulation and (C) with 10 μg/ml PHA-P stimulation was measured after 72, 96 and 120 h by flow cytometry. No significant differences were seen between HD and control for any of the experimental time points or conditions. Statistical analysis was carried out using two-tailed unpaired student’s t tests with a Holm-Šídák correction (alpha = 0.05) for multiple comparisons.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4631523&req=5

pone.0141793.g003: The percentage of proliferating CD3+ T lymphocytes is not affected in HD compared to control.PBMCs were stained with CFSE and the percentage of CD3+ T lymphocytes from the initial culture which divided (A) in the absence of stimulation (B) with 5 μg/ml anti-CD3 and 2 μg/ml anti-CD28 antibody stimulation and (C) with 10 μg/ml PHA-P stimulation was measured after 72, 96 and 120 h by flow cytometry. No significant differences were seen between HD and control for any of the experimental time points or conditions. Statistical analysis was carried out using two-tailed unpaired student’s t tests with a Holm-Šídák correction (alpha = 0.05) for multiple comparisons.

Mentions: The proliferative response of three T lymphocyte populations (all CD3+, CD3+ CD4+ and CD3+ CD8+ cells, gating schematic in S2 Fig) was analysed using a range of statistics as outlined by Roederer [19]. No significant differences were seen in the percentage of CD3+ T lymphocytes from the initial culture that entered cell division (percentage divided) for any of the experimental conditions or time points (Fig 3). Similarly, no significant differences were seen in the average number of divisions each dividing CD3+ T lymphocyte underwent (proliferation index) (Fig 4). Similar results were obtained when the CD4+ and CD8+ subtypes were analysed, with no significant differences being observed for any of the experimental conditions or time points (S3 and S4 Tables). Additional analysis was carried out to determine the average number of divisions all cells in culture underwent (division index) (S5 Table), as well as the percentage of cells in the final culture which had divided at least once (fraction diluted) (S6 Table). Again, no significant differences were seen between the HD and control samples. These results demonstrate that proliferation in response to a stimulus is not impaired in any of the major T lymphocyte populations in HD.


Mutant Huntingtin Does Not Affect the Intrinsic Phenotype of Human Huntington's Disease T Lymphocytes.

Miller JR, Träger U, Andre R, Tabrizi SJ - PLoS ONE (2015)

The percentage of proliferating CD3+ T lymphocytes is not affected in HD compared to control.PBMCs were stained with CFSE and the percentage of CD3+ T lymphocytes from the initial culture which divided (A) in the absence of stimulation (B) with 5 μg/ml anti-CD3 and 2 μg/ml anti-CD28 antibody stimulation and (C) with 10 μg/ml PHA-P stimulation was measured after 72, 96 and 120 h by flow cytometry. No significant differences were seen between HD and control for any of the experimental time points or conditions. Statistical analysis was carried out using two-tailed unpaired student’s t tests with a Holm-Šídák correction (alpha = 0.05) for multiple comparisons.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4631523&req=5

pone.0141793.g003: The percentage of proliferating CD3+ T lymphocytes is not affected in HD compared to control.PBMCs were stained with CFSE and the percentage of CD3+ T lymphocytes from the initial culture which divided (A) in the absence of stimulation (B) with 5 μg/ml anti-CD3 and 2 μg/ml anti-CD28 antibody stimulation and (C) with 10 μg/ml PHA-P stimulation was measured after 72, 96 and 120 h by flow cytometry. No significant differences were seen between HD and control for any of the experimental time points or conditions. Statistical analysis was carried out using two-tailed unpaired student’s t tests with a Holm-Šídák correction (alpha = 0.05) for multiple comparisons.
Mentions: The proliferative response of three T lymphocyte populations (all CD3+, CD3+ CD4+ and CD3+ CD8+ cells, gating schematic in S2 Fig) was analysed using a range of statistics as outlined by Roederer [19]. No significant differences were seen in the percentage of CD3+ T lymphocytes from the initial culture that entered cell division (percentage divided) for any of the experimental conditions or time points (Fig 3). Similarly, no significant differences were seen in the average number of divisions each dividing CD3+ T lymphocyte underwent (proliferation index) (Fig 4). Similar results were obtained when the CD4+ and CD8+ subtypes were analysed, with no significant differences being observed for any of the experimental conditions or time points (S3 and S4 Tables). Additional analysis was carried out to determine the average number of divisions all cells in culture underwent (division index) (S5 Table), as well as the percentage of cells in the final culture which had divided at least once (fraction diluted) (S6 Table). Again, no significant differences were seen between the HD and control samples. These results demonstrate that proliferation in response to a stimulus is not impaired in any of the major T lymphocyte populations in HD.

Bottom Line: However, it is not clear whether or to what extent the adaptive immune system is also involved.The transcriptional profile of T lymphocytes also does not appear to be significantly affected, suggesting that peripheral immune dysfunction in Huntington's disease is likely to be mediated primarily by the innate rather than the adaptive immune system.Finally, this study suggests that the potential use of novel therapeutics aimed at modulating the Huntington's disease innate immune system should not be extended to include the adaptive immune system.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurodegenerative Disease, UCL Institute of Neurology, London, United Kingdom.

ABSTRACT
Huntington's disease is a fatal neurodegenerative condition caused by a CAG repeat expansion in the huntingtin gene. The peripheral innate immune system is dysregulated in Huntington's disease and may contribute to its pathogenesis. However, it is not clear whether or to what extent the adaptive immune system is also involved. Here, we carry out the first comprehensive investigation of human ex vivo T lymphocytes in Huntington's disease, focusing on the frequency of a range of T lymphocyte subsets, as well as analysis of proliferation, cytokine production and gene transcription. In contrast to the innate immune system, the intrinsic phenotype of T lymphocytes does not appear to be affected by the presence of mutant huntingtin, with Huntington's disease T lymphocytes exhibiting no significant functional differences compared to control cells. The transcriptional profile of T lymphocytes also does not appear to be significantly affected, suggesting that peripheral immune dysfunction in Huntington's disease is likely to be mediated primarily by the innate rather than the adaptive immune system. This study increases our understanding of the effects of Huntington's disease on peripheral tissues, while further demonstrating the differential effects of the mutant protein on different but related cell types. Finally, this study suggests that the potential use of novel therapeutics aimed at modulating the Huntington's disease innate immune system should not be extended to include the adaptive immune system.

No MeSH data available.


Related in: MedlinePlus