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. 2013 Oct 14;8(10):e77921.
doi: 10.1371/journal.pone.0077921. eCollection 2013.

Decreased proportion of cytomegalovirus specific CD8 T-cells but no signs of general immunosenescence in Alzheimer's disease

Gabriel Westman  1 , Anna-Karin Lidehall, Peetra Magnusson, Martin Ingelsson, Lena Kilander, Lars Lannfelt, Olle Korsgren, Britt-Marie Eriksson
Affiliations

Decreased proportion of cytomegalovirus specific CD8 T-cells but no signs of general immunosenescence in Alzheimer's disease

Gabriel Westman et al. PLoS One. .

Abstract

Cytomegalovirus (CMV) has been suggested as a contributing force behind the impaired immune responsiveness in the elderly, with decreased numbers of naïve T-cells and an increased proportion of effector T-cells. Immunological impairment is also implicated as a part of the pathogenesis in Alzheimer's disease (AD). The aim of this study was to investigate whether AD patients present with a different CMV-specific CD8 immune profile compared to non-demented controls. Blood samples from 50 AD patients and 50 age-matched controls were analysed for HLA-type, CMV serostatus and systemic inflammatory biomarkers. Using multi-colour flow cytometry, lymphocytes from peripheral blood mononuclear cells were analysed for CMV-specific CD8 immunity with MHC-I tetramers A01, A02, A24, B07, B08 and B35 and further classified using CD27, CD28, CD45RA and CCR7 antibodies. Among CMV seropositive subjects, patients with AD had significantly lower proportions of CMV-specific CD8 T-cells compared to controls, 1.16 % vs. 4.13 % (p=0.0057). Regardless of dementia status, CMV seropositive subjects presented with a lower proportion of naïve CD8 cells and a higher proportion of effector CD8 cells compared to seronegative subjects. Interestingly, patients with AD showed a decreased proportion of CMV-specific CD8 cells but no difference in general CD8 differentiation.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Gating flow-chart.
The CD3+CD8+ subset was identified from the FSC/SSC lymphocyte window, and further analysed for CMV tetramer staining and CD27/CD28/CD45RA/CCR differentiation.
Figure 2a-c
Figure 2a-c. Comparison of proportions of CMV-specific CD8 cells and overall CD4/CD8 ratio in seropositive subjects with Alzheimer´s disease (AD) and non-demented controls (ND).
a) Comparing total cell count for all HLA-types, there is a clear difference with significantly lower proportions of CMV-specific CD8 cells in AD compared to ND group; 1.16 % versus 4.13 % (p=0.0057) b) Comparing only subjects with HLA-A02 tetramer data, there is a trend towards lower proportions of CD8 cells in the AD compared to the ND group; 1.26 % versus 3.07% (p=0.066) c) The overall CD4/CD8-ratio did not differ between groups.
Figure 3
Figure 3. CD27 vs. CD45RA differentiation plot.
No difference in differentiation between AD and ND groups in terms of CD27 and CD45RA expression. Upper right: Naïve. Lower right: Memory. Upper left: Effector.
Figure 4
Figure 4. CCR7 vs. CD45RA differentiation plot.
No difference in differentiation between AD and ND groups in terms of CCR7 and CD45RA expression. Upper right: Naïve. Lower right: Central memory. Upper left: Effector. Lower left: Effector-memory.
Figure 5
Figure 5. CD27 vs. CD28 differentiation plot.
No difference in differentiation between AD and ND groups in terms of CD27 and CD28 expression. Upper right: Early memory and naïve. Lower right: Intermediate memory. Lower left: Late memory.
Figure 6
Figure 6. CD27 vs. CD45RA differentiation plot.
Significant shift from the CD27+CD45RA+ naïve (p=8.13E-05) to CD27-CD45RA+ effector (p=1.76E-06) and CD27-CD45RA- (p=1.17E-04) subsets with CMV status. Upper right: Naïve. Lower right: Memory. Upper left: Effector.
Figure 7
Figure 7. CCR7 vs. CD45RA differentiation plot.
Non-significant trend in shift from the CCR7+CD45RA+ naïve (p=0.062) to the CCR7-CD45RA+ effector (p=0.13) subset with CMV status. Upper right: Naïve. Lower right: Central memory. Upper left: Effector. Lower left: Effector-memory.
Figure 8
Figure 8. CD27 vs. CD28 differentiation plot.
Significant shift from the CD27+CD28+ early memory and naïve (p=3.19E-05) to the CD27-CD28- late memory (p=2.73E-07) subset with CMV status. Upper right: Early memory and naïve. Lower right: Intermediate memory. Lower left: Late memory.
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Grants and funding

This work was funded by grants from The Family Ohlinder-Nielsen’s Foundation, Uppsala University, Landstinget i Uppsala län, Swedish Research Council (2006-2822, 2006-6326 and 2006-3464), Swedish Brain Foundation, Swedish Alzheimer Foundation and Swedish Society of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.