Altered T-Cell Function in Schizophrenia: A Cellular Model to Investigate Molecular Disease Mechanisms

Abstract

Despite decades of research into the aetiology and pathophysiology of schizophrenia, our understanding of this devastating disorder remains incomplete, with adverse consequences for both diagnosis and treatment. Here we investigate whether differences between patients and controls can be observed in peripheral patient tissue, with a view of establishing a means for dynamic investigations into cell function. In vitro stimulation of peripheral blood CD3+ pan T cells with anti-CD3 (clone OKT3) was used to investigate disease-associated cell responses. T cells from both medicated (n = 39), unmedicated (n = 6) and minimally medicated (n = 5) schizophrenia patients were found to have significantly lower proliferative responses to stimulation, compared to well-matched controls (n = 32). Expression of CD3 and TCR (T cell receptor) αβ chains was equivalent between patients and controls, ensuring equal stimulation with anti-CD3, and there was no significant difference in the proportions of CD4+ and CD8+ T cells between samples (n = 12). Lower T cell proliferation in schizophrenia patients was not found to result from deficient early tyrosine phosphorylation signalling or lower IL-2 (interleukin-2) production, as these parameters were similar between patients and controls, as was the expression of CD25, the IL-2 receptor α chain. Analysis of CD45 isoforms, however, revealed that patients had a significantly greater percentage of CD8+ and CD4+ CD45RA+ cells before stimulation and significantly higher fluorescence intensity of CD45RA on CD4+ and CD8+ cells before and after stimulation. There was significantly higher expression of CD45 RB on both CD4+ and CD8+ unstimulated cells, with a trend towards lower numbers of CD45RO+ T cells in patient blood. Gene expression analysis in freshly isolated T cells from six minimally treated or first onset patients and six controls was carried out using human whole-genome CodeLink microarrays to identify functional pathways that may affect the ability of patient cells to respond to stimulation. Functional profiling showed prominent transcript changes in categories pertaining to cell cycle machinery, intracellular signalling, oxidative stress and metabolism. Intriguingly, chromosomal location analysis of genes significantly altered between schizophrenia and controls revealed clusters at 1p36, 1q42 and 6p22, which have previously been identified as strong susceptibility loci for schizophrenia.

Increased α-Defensins as a Blood Marker for Schizophrenia Susceptibility

“…There is increasing evidence, both from the literature and from studies carried out within our own group, to suggest that disease-related changes can be detected outside the brain (11,13,14). Various immune alterations have been reported previously in schizophrenia (15)(16)(17)(18), and disease-related changes are detectable in T cells (19). In the present study we extended our search for biomarkers to proteomics profiling of peripheral blood CD3 ϩ T cells.…”

Biomarkers in schizophrenia: A focus on blood based diagnostics and theranostics

“…The immune responses to changes of cellular environ ment have been measured and reported to be altered in people with Sz [62,65,66] . For example, out of 107 immune molecules, less IL-18 and more S100A12 (ENRAGE) were secreted by blood cells in ex vivo cultures obtained from firstonset people with Sz compared to controls following stimulation condition with a T cell stimulator (i.e., anti-CD28/CD49d) [66] , an effect replicated in an independent cohort [66] .…”

Differential effects on T-cell function following exposure to serum from schizophrenia smokers

“…Long-term activation could then lead to desensitization of the proliferation responses as indicated by a reduced proliferative rate of schizophrenia patient-derived T cells, implying that patient T cells have become refractory to stimulation and respond significantly less to in vitro stimulation. 17,18,41 T-cell activation in the patient's body, as shown here through elevated levels of CD25 high and CD69 high , could furthermore help to recruit T cells to cross the blood-brain barrier to foster communication between the central nervous system and the immune system. Previous studies have shown that T cells have beneficial effects on a damaged central nervous system.…”

“…[13][14][15][16] T lymphocytes have integral function in cell-mediated immunity and are involved in host defence against infectious agents. Peripheral changes in the immune system of schizophrenia patients, such as decreased cellular immune response 17,18 and altered cytokineexpression, 19 have been reported. However, these immunological findings are inconsistent and controversial due to different methodological approaches, the heterogeneity of sample sourcing and acquisition, as well as lack of controls for confounding factors such as smoking.…”