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Altered expression of costimulatory molecules in dementias.

ABSTRACT: Although the expression of co-stimulatory molecules plays an important role in the immune system, only little is known about their regulation in dementias. Therefore, we determined the expression of CD28, ICOS (CD278) and CTLA-4 (CD152) by CD4 + and CD8 + T cells in the peripheral blood of patients with mild cognitive impairment (MCI; N = 19), Alzheimer's disease (AD; N = 51), vascular dementia (VD; N = 21) and frontotemporal dementia (FTD; N = 6) at the point in time of diagnosis compared to 19 non-demented elderly persons. The expression of CD28 and ICOS by CD4 + and CD8 + T cells was not changed in AD, FTD or VD patients. The expression of the negative regulator CTLA-4 was increased by CD4 + T cells from AD and FTD patients and by CD8 + T cells from VD patients. The classification of the AD patients according to the severity of the disorder showed stage-dependent alterations of CD28, ICOS and CTLA-4 expression. In AD patients, the correlation analysis showed an association between the decline in CD28 + T cells and the increase in CTLA-4 + T cells with cognitive decline, measured by the mini-mental state examination (MMSE), tau proteins and Amyloid-β, important AD biomarkers in cerebrospinal fluid (CSF). In FTD patients, a positive association between Q Albumin, a marker for blood-CSF-barrier function, and CD28 and a negative correlation between Q Albumin and ICOS expression were determined. Our data suggest a dysregulated balance between the expression of negative and positive co-stimulatory molecules by T cells in AD patients, which might contribute to chronic inflammation observed in dementia.

SUBMITTER: Busse S

PROVIDER: S-EPMC9279221 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundBovine luteal parenchymal cells express class II major histocompatibility complex (MHC) molecules and stimulate class II MHC-dependent activation of T cells in vitro. The ability of a class II MHC-expressing cell type to elicit a response from T cells in vivo is also dependent on expression of costimulatory molecules by the antigen presenting cell and delivery of a costimulatory signal to the T cell. Whether bovine luteal parenchymal cells express costimulatory molecules and can deliver the costimulatory signal is currently unknown.MethodsBovine luteal tissue was collected during the early (day 5; day of estrus = day 0), mid (day 11-12), or late (day 18) luteal phase of the estrous cycle, and at 0, 0.5, 1, 4, 12 or 24 hours following administration of PGF2alpha to cows on day 10 of the estrous cycle. Northern analysis was used to measure CD80 or CD86 mRNA concentrations in luteal tissue samples. Mixed luteal parenchymal cell cultures and purified luteal endothelial cell cultures were prepared, and real-time RT-PCR was used to examine the presence of CD80 and CD86 mRNA in each culture type. Monoclonal antibodies to CD80 and CD86 were added to a mixed luteal parenchymal cell-T cell co-culture in vitro T cell proliferation assay to assess the functional significance of costimulatory molecules on activation of T lymphocytes by luteal parenchymal cells.ResultsNorthern analysis revealed CD80 and CD86 mRNAs in luteal tissue, with greatest steady-state concentrations at midcycle. CD80 and CD86 mRNAs were detected in mixed luteal parenchymal cell cultures, but only slight amounts of CD80 (and not CD86) mRNA were detected in cultures of luteal endothelial cells. Luteinizing hormone, PGF2alpha and TNF-alpha were without effect on concentrations of CD80 or CD86 mRNA in mixed luteal parenchymal cells cultures. Anti-CD80 or anti-CD86 monoclonal antibodies inhibited T cell proliferation in the in vitro T cell proliferation assay.ConclusionIt can be concluded from this study that parenchymal cells within the bovine CL express functional costimulatory molecules that facilitate interactions between with T cells, and these components of the antigen presentation pathway are expressed maximally in the midcycle CL.

Project description:Major depressive disorder (MDD) is associated with physiological changes commonly observed with increasing age, such as inflammation and impaired immune function. Age-related impaired adaptive immunity is characterized by the loss of naive T-cells and the reciprocal accumulation of memory T-cells together with the loss of T-cell co-stimulatory molecules. Additionally, the presence and activity of cytomegalovirus (CMV) alters the architecture of the T-cell compartment in a manner consistent with premature aging. Because CMV is also thought to reactivate with psychological stress, this study tested whether MDD influences age-related phenotypes of T-cell populations in the context of CMV infection in young and middle-aged adults. Morning blood samples from volunteers with a DSM-IV diagnosis of MDD (n = 98, mean age(SD) = 36(10) years, 74.5% female, 57.1% CMV+) and comparison controls (n = 98, mean age(SD) = 34(10) years, 68.4% female, 51.0% CMV+) were evaluated for CMV IgG antibody status and the distribution of late differentiated (CD27-CD28-) cells within CD4+ and CD8+ T-cell subsets, i.e. naive (CCR7+CD45RA+), effector memory (EM, CCR7-CD45RA-), central memory (CM, CCR7+CD45RA-) and effector memory cells re-expressing CD45RA (EMRA, CCR7-CD45RA+). Mixed linear regression models controlling for age, sex, ethnicity and flow cytometry batch showed that CMV seropositivity was associated with a reduction in naive T-cells, expansion of EMRA T-cells, and a greater percent distribution of CD27-CD28- cells within CD4+ and CD8+ memory T-cell subsets (p's < 0.004), but there was no significant effect of MDD, nor any significant interaction between CMV and diagnosis. Unexpectedly, depressed men were less likely to be CMV+ and depressed women were more likely to be CMV+ than sex-matched controls suggesting a possible interaction between sex and MDD on CMV susceptibility, but this three-way interaction did not significantly affect the T-cell subtypes. Our findings suggest that depression in young and middle-aged adults does not prematurely advance aging of the T-cell compartment independently of CMV, but there may be significant sex-specific effects on adaptive immunity that warrant further investigation.

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Altered expression of costimulatory molecules in dementias.

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