Dramatic Shifts in Circulating CD4 but not CD8 T Cell Subsets in Mild Alzheimer's Disease

Abstract

The distribution of peripheral T cell subsets in young and healthy old people is markedly different, characterized by decreased numbers of naïve cells and increased numbers and clonal expansions of memory cells, predominantly in the CD8+ MHC class I-restricted subset. Here, however, we document dramatic alterations in naïve and memory subsets of CD4+ cells in patients with mild Alzheimer's disease (AD), with greatly decreased percentages of naïve cells, elevated memory cells, and increased proportions of CD4+ but not CD8+ cells lacking the important costimulatory receptor CD28. CD4+CD25(high) potentially T regulatory cells with a naïve phenotype are also reduced in AD patients. Together these data provide stronger evidence than hitherto presented for more highly differentiated CD4+ as well as CD8+ T cells in AD patients, consistent with an adaptive immune system undergoing persistent antigenic challenge and possibly manifesting dysregulation as a result.

Immune profiling of Alzheimer patients

“…Alternatively the shift from naïve to late memory CD4+ cells in AD patients can be the result of the capture of Aβ by local APC in the brain and the migration of these cells towards secondary lymph nodes inducing T cell stimulation, as suggested by Monsonego et al (Monsonego et al, 2003). The present results are consistent with our previous report of a pilot study of mild AD patients (Larbi et al, 2009), but extend that study beyond the diagnosis of mild AD to include moderate AD. Moreover, the employment of a different set of markers to define naïve and differentiated memory cells in these two studies in patients from two different countries, nonetheless with consistent results, suggests that these findings are likely to be robust.…”

“…These data are not in complete agreement with other reports of no differences in the percentage and absolute number of CD3+ T cells, NK cells or CD4+ and CD8+ T cells (Speciale et al, 2007). In our own pilot study we showed that major changes are seen within the CD4+ T cell subset in mild AD patients compared to healthy elderly controls (Larbi et al, 2009) whereas the more marked changes in the CD8 subsets were seen equally in both patients and age-matched controls. To confirm and extend our previous findings in a different population (Italian not Canadian), here we tested a larger group of AD patients (n = 40, one group of mild and one group of moderate AD) compared to healthy old (n = 21) and young subjects (n = 11) using multiparameter flow cytometry, including new markers to better characterize the immunological profile of these patients.…”

“…In our previous paper we also showed a higher percentage of CD4 + CD25+ putative Treg cells in AD compared to healthy controls (Larbi et al, 2009). However, the IL 2rα chain (CD25) expressed on Tregs is also expressed on activated cells.…”

“…Within the T cell population, a slight increase of the percentage of CD4+ and a decrease of CD8+ lymphocytes was found (RichartzSalzburger et al, 2007). We recently reported a significant reduction of the percentage of naïve CD4+ cells (CD45RA +CCR7+), and an increase of effector memory (CD45RA-CCR7-) and TEMRA (CD45RA+CCR7-) cells in a pilot study of Canadian AD patients (Larbi et al, 2009) compared to age-matched controls. A reduction of CD4+CD25 high cells, considered as potentially Treg cells, was also found (Larbi et al, 2009).…”

“…We recently reported a significant reduction of the percentage of naïve CD4+ cells (CD45RA +CCR7+), and an increase of effector memory (CD45RA-CCR7-) and TEMRA (CD45RA+CCR7-) cells in a pilot study of Canadian AD patients (Larbi et al, 2009) compared to age-matched controls. A reduction of CD4+CD25 high cells, considered as potentially Treg cells, was also found (Larbi et al, 2009). No differences were discernible between AD patients and controls within the CD8 compartment because the effects of age were already so marked in the latter.…”