Maladaptation to mental stress mitigated by the adaptive immune system via depletion of naturally occurring regulatory CD4+CD25+ cells

Abstract

Peripheral cellular immunity was recently shown to play a critical role in brain plasticity and performance. The antigenic specificity of the participating T cells, however, was not investigated, and nor was their relevance to psychological stress. Here we show, using a mouse model, that adaptive immunity mitigates maladaptation to the acute psychological stress known to trigger abnormal behaviors reminiscent of human post-traumatic stress disorder. Assessment of behavioral adaptation (measured by the acoustic startle response and avoidance behavior) in mice after their exposure to predator odor revealed that maladaptation was several times more prevalent in T cell-deficient mice than in their wild-type counterparts. A single population of T cells reactive to central nervous system (CNS)-associated self-protein was sufficient to endow immune-deficient mice with the ability to withstand the psychological stress. Naturally occurring CD4+CD25+ regulatory T cells were found to suppress this endogenous anti-stress attribute. These findings suggest that T cells specific to abundantly expressed CNS antigens are responsible for brain tissue homeostasis and help the individual to cope with stressful life episodes. They might also point the way to development of immune-based therapies for mental disorders, based either on up-regulation of T cells that partially cross-react with self-antigens or on weakening of the activity of regulatory T cells.

Psychoneuroimmunology of Early-Life Stress: The Hidden Wounds of Childhood Trauma?

“…Lymphocyte trafficking to the brain is likely protective in the face of stress. Indeed, mice who showed greater lymphocyte trafficking in response to predator odor developed lower anxiety levels and weaker acoustic startle response, and showed faster recovery to pre-stress hippocampal brain-derived neurotrophic factor (BDNF) levels (Cohen et al, 2006;Lewitus et al, 2008). These protective effects are thought to be due to modulation of the stress-induced microglia activation by invading T cells and, thus, to reduction in secondary neuronal damage (Moalem et al, 1999;Yoles et al, 2001).…”

“…These protective effects are thought to be due to modulation of the stress-induced microglia activation by invading T cells and, thus, to reduction in secondary neuronal damage (Moalem et al, 1999;Yoles et al, 2001). Lymphocyte trafficking to the brain also generates memory T cells reactive to CNS antigens (likely signaling cellular damage under stress), which build immune memory and thereby boost secondary adaptive immune response and resilience in the face of subsequent stressors (Cohen et al, 2006). Of note, inoculation (vaccination and immunization) with a CNS-derived peptide has been associated with lower anxiety levels, weaker acoustic startle response, and faster recovery to pre-stress BDNF levels in rodents exposed to predator odor (Lewitus et al, 2008).…”

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

“…15 Adaptive immunity in coping with mental stress Recently, we found an association between T cells and adaptation to psychological stress. 16 In these studies, we used the predator odor model as the psychological stressor. This stress model was shown to result in a long-term effect on both behavioral (reflecting psychological) and physiological functioning, reminiscent of posttraumatic stress disorder (PTSD) in humans.…”

“…However, transgenic mice overexpressing autoreactive T-cells reactive to the CNS-related self-antigen, myelin basic protein (MBP), exhibited reduced incidence of PTSD-like symptoms in response to predator odor relative to their matched controls. 16 These results led us to ask whether T-cells traffic to the CNS after intense experiences, and whether these T cells can become memory T cells and better protect the CNS after a second stress episode.…”

The emergence of a new science of the mind: immunology benefits the mind

“…[4][5][6][7] Thus, for example, it has been commonly accepted that mental stress (depending on its severity) either harnesses immune cells to support the body's function (excluding that of the brain) or suppresses healing; 8 however, the possibility that circulating immune cells may actually protect the brain's function from the consequences of stress was only recently recognized. 9,10 (Cover page) The novel dimensions that were identified in the cross-talk between the brain and the immune system are focused on understanding how the peripheral immune system contributes to brain plasticity, and in cases of brain pathologies, to reveal how immune insufficiency deprives the brain of necessary assistance required for normal behavior, cognition, mental activity and repair. [11][12][13][14][15] This transition in understanding the immune system-brain interface has a direct impact on the directions of research attempting to reveal the mystery of brain diseases and aging.…”