T regulatory cells as a potential therapeutic target in psychosis? Current challenges and future perspectives

Author(s)

Corsi-Zuelli, Fabiana ; Deakin, Bill ; Lima, Mikhael Haruo Fernandes de ; Qureshi, Omar ; Barnes, Nicholas M. ; Upthegrove, Rachel ; Louzada-Junior, Paulo ; Del-Ben, Cristina Marta

• Document type: Journal article
• Source: BRAIN, BEHAVIOR, & IMMUNITY - HEALTH; v. 17, p. 14-pg., 2021-11-01.

Abstract

Many studies have reported that patients with psychosis, even before drug treatment, have mildly raised levels of blood cytokines relative to healthy controls. In contrast, there is a remarkable scarcity of studies investigating the cellular basis of immune function and cytokine changes in psychosis. The few flow-cytometry studies have been limited to counting the proportion of the major classes of monocyte and lymphocytes without distinguishing their pro- and anti-inflammatory subsets. Moreover, most of the investigations are cross-sectional and conducted with patients on long-term medication. These features make it difficult to eliminate confounding of illness-related changes by lifestyle factors, disease duration, and long exposure to antipsychotics. This article focuses on regulatory T cells (Tregs), cornerstone immune cells that regulate innate and adaptive immune forces and neuroimmune interactions between astrocytes and microglia. Tregs are also implicated in cardio-metabolic disorders that are common comorbidities of psychosis. We have recently proposed that Tregs are hypofunctional ('h-Tregs') in psychosis driven by our clinical findings and other independent research. Our h-Treg-glial imbalance hypothesis offers a new account for the co-occurrence of systemic immune dysregulation and mechanisms of psychosis development. This article extends our recent review, the h-Treg hypothesis, to cover new discoveries on Treg-based therapies from pre-clinical findings and their clinical implications. We provide a detailed characterisation of Treg studies in psychosis, identifying important methodological limitations and perspectives for scientific innovation. The outcomes presented in this article reaffirms our proposed h-Treg state in psychosis and reveals emerging preclinical research suggesting the potential benefit of Treg-enhancing therapies. There is a clear need for longitudinal studies conducted with drug-naive or minimally treated patients using more sophisticated techniques of flow-cytometry, CyTOF expression markers, and in vitro co-culture assays to formally test the suppressive capacity of Tregs. Investment in Treg research offers major potential benefits in targeting emerging immunomodulatory treatment modalities on person-specific immune dysregulations. (AU)

• FAPESP's process: 12/05178-0 - Schizophrenia and other psychotic disorders: social and biological determinants
• Grantee: Paulo Rossi Menezes
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 20/02642-3 - Characterization of the TIGIT+ T regulatory cell subset in response to therapy with disease-modifying anti-rheumatic drugs in patients with Rheumatoid Arthritis
• Grantee: Mikhael Haruo Fernandes de Lima
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/13229-2 - Inflammatory profile in the general population: transdiagnostic dimensions in the context of the psychosis continuum
• Grantee: Fabiana Maria das Graças Corsi Zuelli
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 21/07448-3 - Immunophenotype of immune-active psychosis patients and the role of interleukin-6
• Grantee: Fabiana Maria das Graças Corsi Zuelli
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate