Is There a Role for the Adaptive Immune System in Immune to Brain Communication?
Given the results of experimental models using real life infection, which, when given at physiological doses, show different outcomes when compared to selected innate immune stimuli, it is plausible that the adaptive immune system is involved in regulating how the immune system communicates with our brain. It is well known that adaptive immune responses progressively decline with age [69, 70].
Increasing experimental data suggest that T cells may also contribute to the regulation of microglia and neurons. For example, nude and severe combined immune deficient (SCID) mice that lack T cells, underperform in the Morris water maze, suggesting a reduced cognitive ability and adoptive transfer of splenocytes from wild-type donors resulted in improved learning behaviour [71, 72]. Similar results were obtained following the depletion of CD4+, but not CD8+ T cells , implying that CD4 T cells play a role in regulating neural function and/or plasticity. Modulation of T cells in experimental models of neurodegeneration further support these observations. Treatment with the immunosuppressive drug Tacrolimus (FK506), a molecule that inhibits the development and proliferation of T cells by neutralizing IL-2, significantly increased the survival of dopaminergic neurons following AAV-mediated overexpression of a-synuclein. Remarkably, no change in a-synuclein aggregation was observed, but FK506 significantly lowered the infiltration of both CD4+ T helper and CD8+ cytotoxic T cells and reduced the number of CD11b+microglial cells in the affected brain area, without changing CD68 and MHCII expression . Interestingly, genetic loss of tau results in a reduction in microglia number and activation, and administration of FK506 to young Tau transgenic mice (P301S) attenuates tau pathology and increased lifespan, thereby linking neuroinflammation to early progression of tauopathies . Similarly, acute treatment of APP transgenic mice (Tg2576) with FK506 improves memory function . In accord, treatment of APP/PS1 mice with Copaxone (Glatiramer Acetate), a drug that breaks tolerance and promotes T cells development to brain antigens, results in decreased amyloid load associated with reduced cognitive decline and a microglial switch towards a neuroprotective phenotype . However, aged APP/PS1 mice treated with live Bordetella pertussis results in a significant increase in effector CD4+ T cell infiltration that correlates with increase amyloid load . These observations imply that the timing of activation and type of CD4+ T cell, may determine if the adaptive immune response is neuroprotective or not.