Figure 3.

Sources and non-canonical functions of IFN-γ and IL-10 in the brain. (A) The cytokine milieu in and around the brain is tightly controlled to allow beneficial, hemostatic low-level autoimmunity but prevent excessive inflammation. Thus, pro-inflammatory local IFN-γ which promotes neural differentiation and synaptic pruning is restrained by local presence of anti-inflammatory, stemness preserving, and synapses formation supporting IL-10. The boxes summarize further unique and shared functions of these cytokines in metabolism, hormone regulation, and behavioral control (see text for more details). (B) The origins of IFN-γ- and IL-10 in the central nervous system (CNS) are not fully delineated. Sources include production by local tissue-resident cells such as microglia and astrocytes, influx from the periphery via a compromised blood-brain barrier (BBB), and/or, production by T cells residing in or are adjacent to the brain parenchyma, meninges, choroid plexus, circumventricular organs and ventricles. Brain-associated T cells enter these regions mainly via the recently discovered meningeal lymphatics, and/or extravasation through endothelial cells lining blood vessels within the CNS, and/or crossing the BBB involving an ICAM-1- or VCAM-1-mediated mechanisms (insert). Brain T cells can be resident or patrolling and mediate immunosurveillance and protection against infection but also the normal development and physiological activities of the brain, including host behavior and emotions via production of effector molecules (cytokines, neuro-active metabolites, neurotransmitters, etc., see text for more details). Moreover, CD4⁺ T cells have been shown to produce neurotransmitters as well as further neuromodulating agents and metabolites such as glutamate and lactate, regulate neural synapse formation and mediate neural transduction. Of note, the effects of T cells on neural functions and emotions are complex and strongly influenced by spatial and temporal context and micromilieu in the brain.