T cell deficiency leads to cognitive dysfunction: Implications for therapeutic vaccination for schizophrenia and other psychiatric conditions

Abstract

The effects of the adaptive immune system on the cognitive performance and abnormal behaviors seen in mental disorders such as schizophrenia have never been documented. Here, we show that mice deprived of mature T cells manifested cognitive deficits and behavioral abnormalities, which were remediable by T cell restoration. T cell-based vaccination, using glatiramer acetate (copolymer-1, a weak agonist of numerous self-reactive T cells), can overcome the behavioral and cognitive abnormalities that accompany neurotransmitter imbalance induced by (+)dizocilpine maleate (MK-801) or amphetamine. The results, by suggesting that peripheral T cell deficit can lead to cognitive and behavioral impairment, highlight the importance of properly functioning adaptive immunity in the maintenance of mental activity and in coping with conditions leading to cognitive deficits. These findings point to critical factors likely to contribute to age- and AIDS-related dementias and might herald the development of a therapeutic vaccination for fighting off cognitive dysfunction and psychiatric conditions.

Therapeutic Implications of Brain–Immune Interactions: Treatment in Translation

“…From a therapeutic standpoint, urging T cells to traffic to the brain via administration of a CNS-related antigen has been shown to exhibit both an antianxiety and antidepressant effect depending on the animal model (Lewitus and Schwartz, 2009;. Along similar lines, T cells have been shown to be essential for normal cognitive function such that T cell-deficient animals exhibit impaired learning and memory as revealed by Morris water maze, Barnes maze, and radial arm maze that can be reversed by the adoptive transfer of T cells (Kipnis et al, 2004;Ziv et al, 2006). Moreover, experiments using RAG-1 knockout mice (that are deficient in mature B and T cells) have revealed that long-term deficiencies in CD4+ T cells are associated with impaired behavioral responses including increased digging and marble-burying activities compared with wild-type mice (Rattazzi et al, 2013).…”

Behavioral immunization: immunity to self-antigens contributes to psychological stress resilience

“…A decade ago, our laboratory discovered the importance of the self-reactive T cells in the repair of central nervous system (CNS) injury. 5 The protective capacity of autoimmune cells was further shown in several models of CNS pathology including mechanical injury, 5,6 Alzheimer's disease, 7 Parkinson's disease 8 and imbalances in neurotransmitter levels, 9 as well as non-CNS processes such as skin wound healing. 10 The neuroprotective immune response is a physiological response that is spontaneously evoked after trauma.…”

“…6,12,13 In addition to the role of CNSspecific T cells in CNS repair, our group has found that adaptive immune cells are key players in CNS maintenance under nonpathological conditions, especially in hippocampal plasticity. 9,14 We showed that autoreactive T cells are needed to support hippocampal-dependent learning and memory tasks, as well as for the regulation of adult hippocampal neurogenesis and neurotrophic factor production, 14 possibly by regulating microglial phenotype. 15 Adaptive immunity in coping with mental stress Recently, we found an association between T cells and adaptation to psychological stress.…”

CD4-Positive T Lymphocytes Provide a Neuroimmunological Link in the Control of Adult Hippocampal Neurogenesis

“…In models of general immune deficiency, impairment in cognitive function has been shown (22), and Brynskikh et al (23) described a role for T cells in cognition and behavior. In neither case, however, a potential relation to adult neurogenesis has been addressed.…”