IL-2 is essential for T-helper regulatory (Treg) cell function and self-tolerance, and dysregulation of both endogenous brain and peripheral IL-2 gene expression may have important implications for neuronal injury and repair. We used an experimental approach combining mouse congenic breeding and immune reconstitution to test the hypothesis that the response of facial motoneurons to axotomy injury is modulated by the combined effects of IL2-mediated processes in the brain that modulate it’s endogenous neuroimmunological milieu, and IL2-mediated processes in the peripheral immune system that regulate T cell function (i.e., normal vs. autoreactive Treg-deficient T cells). This experimental strategy enabled us test our hypothesis by disentangling the effect of normal versus autoreactive T lymphocytes from the effect of endogenous brain IL-2 on microglial responsivness (microglial phagocytic clusters normally associated with dead motoneurons and MHC2+ activated microglia) and T cell trafficking, using the facial nerve axotomy model of injury. The results demonstrate that the loss of both brain and peripheral IL-2 had an additive effect on numbers of microglial phagocytic clusters at day 14 following injury, whereas the autoreactive status of peripheral T cells was the primary factor that determined the degree to which T cells entered the injured brain and contributed to increased microglial phagocytic clusters. Changes in activated MHC2+ microglial in the injured FMN were associated with loss of endogenous brain IL-2 and/or peripheral IL-2. This model may provide greater understanding of the mechanisms involved in determining if T cells entering the injured central nervous system (CNS) have damaging or proregenerative effects.
Emerging data from our lab and others suggested that dysregulation of the brain’s endogenous neuroimmunological milieu may occur with the loss of brain IL-2 gene expression and be involved in initiating processes that lead to CNS autoimmunity. We sought to test our working hypothesis that IL-2 deficiency induces endogenous changes in the CNS that play a key role in eliciting T cell homing into the brain. To accomplish this goal, we used an experimental approach that combined mouse congenic breeding and immune reconstitution. In congenic mice without brain IL-2 (two IL-2 KO alleles) that were reconstituted with a normal wild-type immune system, the loss of brain IL-2 doubled the number of T cells that trafficked into the brain in all regions quantified (hippocampus, septum, and cerebellum) compared to mice with two wild-type brain IL-2 alleles and a wild-type peripheral immune system. Congenic mice with normal brain IL-2 (two wild-type IL-2 alleles) that were immune reconstituted with autoreactive Treg-deficient T cells from IL-2 KO mice developed the expected peripheral autoimmunity (splenomegaly) and had a comparable doubling of T cell trafficking into the hippocampus and septum, whereas they exhibited an additional two-fold proclivity for the cerebellum over the septohippocampal regions. Unlike brain trafficking of wild-type T cells, the increased homing of IL-2 KO T cells to the cerebellum was independent of brain IL-2 gene expression. These findings demonstrate that brain IL-2 deficiency induces endogenous CNS changes that may lead to the development of brain autoimmunity, and that autoreative Treg-deficient IL-2 KO T cells trafficking to the brain could have a proclivity to induce cerebellar neuropathology.
Although many studies have documented peripheral immune alterations in patients with psychiatric and neurological disorders, almost all these data in humans are correlative. The actions of IL-2 on neurodevelopment, function, and disease are the result of both IL-2's actions in the peripheral immune system and intrinsic actions in the CNS. Determining if, and under what conditions (e.g., development, acute injury) these different actions of IL-2 are operative in the brain is essential to make advances in understanding the multifaceted affects of IL-2 on CNS function and disease. Mouse models have provided ways to obtain new insights into how the complex biology of a cytokine such as IL-2 can have simultaneous, dynamic effects on multiple systems (e.g., regulating homeostasis in the brain and immune system, autoimmunity that can affect both systems). Here we describe some of the relevant literature and our research using different mouse models. This includes models such as congenic IL-2 knockout mice bred on immunodeficient backgrounds coupled with immune reconstitution strategies used to dissect neuroimmunological processes involved in the development of septohippocampal pathology, and test the hypothesis that dysregulation of the brain's endogenous neuroimmunological milieu may occur with the loss of brain IL-2 gene expression and be involved in initiating CNS autoimmunity. Use of animal models like these in the field of psychoneuroimmunology may lead to critical advances into our understanding of the role of brain cytokines and autoimmunity in neurodegenerative diseases (e.g., Alzheimer's disease), neurodevelopmental disorder (e.g., autism, schizophrenia), and autoimmune diseases including multiple sclerosis.
Brain-derived interleukin-2 (IL-2) has been implicated in diseases processes that arise during CNS development (e.g., autism) to neurodegenerative alterations involving neuroinflammation (e.g., Alzheimer’s disease). Progress has been limited, however, because the vast majority of current knowledge of IL-2’s actions on brain function and behavior is based on the use exogenously administered IL-2 to make inferences about the function of the endogenous cytokine. Thus, to identify the cell-type(s) and regional circuitry that express brain-derived IL-2, we used B6.Cg-Tg/ IL2-EGFP17Evr (IL2p8-GFP) transgenic mice, which express green fluorescent protein (GFP) in peripheral immune cells known to produce IL-2. We found that the IL2-GFP transgene was localized almost exclusively to NeuN-positive cells, indicating that the IL-2 is produced primarily by neurons. The IL2-GFP transgene was expressed in discrete nuclei throughout the rostral-caudal extent of the brain and brainstem, with the highest levels found in the cingulate, dorsal endopiriform nucleus, lateral septum, nucleus of the solitary tract, magnocellular/gigantocellular reticular formation, red nucleus, entorhinal cortex, mammilary bodies, cerebellar fastigial nucleus, and posterior interposed nucleus. Having identified IL-2 gene expression in brain regions associated with the regulation of sensorimotor gating (e.g., lateral septum, dorsal endopiriform nucleus, entorhinal cortex, striatum), we compared prepulse inhibition (PPI) of the acoustic startle response in congenic mice bred in our lab that have selective loss of the IL-2 gene in the brain versus the peripheral immune system, to test the hypothesis that brain-derived IL-2 plays a role in modulating PPI. We found that congenic mice devoid of IL-2 gene expression in both the brain and the peripheral immune system, exhibited a modest alteration of PPI. These finding suggest that IL2p8-GFP transgenic mice may be a useful tool to elucidate further the role of brain-derived IL-2 in normal CNS function and disease.
IntroductionThe idea that damaged neurons may lose their phenotype and/or atrophy rather than die, has intrigued neuroscientists for more than two decades in the field of neurodegeneration research. This remarkable and potentially promising form of neuronal plasticity has been demonstrated in different models of central nervous system (CNS) injury [1][2][3][4], and may be generalizable to different types of neurons and neuropathology in the CNS. Understanding the mechanisms by which neurons survive such insults, and how interactions between complex systems (i.e., the nervous and immune systems) promote survival, are essential to devise novel and more effective treatments for human neurodegenerative diseases. In this paper, we present some of our lab's neuroimmunology research that suggests that both peripheral T cells entering the CNS and brain-derived interleukin-2 (IL-2) play significant roles in these intriguing processes by which neurons appear to survive with the potential to rejuvenate their normal phenotype and regain function. The first half of the review discusses the role that normal T cells play in neuronal preservation and recovery in models of motoneuron injury, and relate that to how immunosenescence, the gradual deterioration of the immune system due to advanced age, may contribute to loss of function and vulnerability in the aging brain. In the second half, we review our research that has identified important actions of brain-derived IL-2 in the maintenance of septohippocampal cholinergic projection neurons, circuitry involved in cognition that has been found to be altered in some forms of neurodegenerative disease in humans. T lymphocytes, Neuronal Atrophy And Regeneration T cells and CNS functionThe question of whether the immune system is actively involved in the maintenance and protection of the CNS has been explored over the last decade and the term "protective autoimmunity" has emerged. It has been demonstrated that the peripheral immune system contributes significantly to the outcome of neuronal trauma during toxic, ischemic, hemorrhagic, infective, degenerative, metabolic and immune-mediated insults and also assists in the process of repair after injury [5]. The role of T cells in the CNS is complicated as evidenced by conflicting data emerging from different models; however multiple studies have made it clear that T lymphocytes have important effects on neuronal integrity and function in the CNS. Under normal conditions, continuous immune surveillance of the CNS occurs by small numbers of circulating peripheral T lymphocytes [6,7]. During pathogenic states such as multiple sclerosis and infection, it is well established that the presence of T cells in the brain can have detrimental effects, however, in other contexts T cells act in concert with glial cells to promote neuroprotection and survival. Perhaps one of the best examples of such a neuroprotective role of peripheral immunity is in the facial nerve axotomy model where T cells slow the rate of neurodegeneration and neuronal loss [8,...
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