No abstract

Numerous methods of T cell depletion lead to impairment of learning and memory function in mice. While adoptive transfer of whole splenocytes rescues learning behavior impairments, the precise sub-population and antigenic specificity of the T cells mediating the rescue remains unknown. Using several transgenic mouse models in combination with adoptive transfers, we demonstrate the necessity of an antigen-specific CD4+ T cell compartment in normal spatial learning and memory, as measured by the Morris water maze (MWM). Moreover, transfer of a monoclonal T cell population reactive to the central nervous system (CNS) antigen, myelin oligodendrocyte glycoprotein (MOG), was sufficient to improve cognitive task performance in otherwise impaired OTII mice, raising the possibility that the antigen-specificity requirement of pro-cognitive T cells may be directed against CNS-derived self-antigens.

No abstract

The traditional view of the central nervous system (CNS) as an immune-privileged organ yielded a longstanding perception of such interactions—as seen for example in multiple sclerosis (MS) 1, 2—as intrinsically destructive. This notion is changing with the identification of several homeostatic functions attributable to beneficial T-cell/CNS interaction 3, for example in hippocampal-dependent learning 4 and stress response paradigms 5, and in models of neurodegeneration and CNS injury 6. Here we provide insights into the maintenance, and dynamics of the meningeal T-cell repertoire. We show that meningeal T-cell composition is coupled to the CNS-draining deep cervical lymph nodes (dCLNs), whose surgical removal interrupted the normal flow of meningeal T-cells and resulted in cognitive impairment.

A r t i c l e A m e n d m e n t s2 5 4 7

MRL/MpJ-Fas(lpr) (MRL/lpr) mice are an accepted animal model to study human systemic lupus erythematosus. We tested if a commonly used analgesic (buprenorphine hydrochloride) would reduce pain and distress in these mice without impacting the progression of autoimmune disease. Female MRL/lpr mice were randomly separated into four groups. Experimental groups received cyclophosphamide (25 mg/kg i.p. weekly), buprenorphine (0.09 mg/kg/mouse/day via drinking water), or cyclophosphamide+buprenorphine from 11 to 21 weeks of age. Controls received no treatments. Mice were monitored daily by a licensed veterinarian (blinded observer) and assigned a score weekly on parameters associated with pain and distress as well as progression of disease. Proteinuria was measured weekly, and serum anti-dsDNA antibody levels were determined at 11, 15, and 18 weeks of age. At 21 weeks of age, the animals were euthanized and the kidneys and spleens were removed for evaluation. Regardless of the parameter observed, buprenorphine did not significantly decrease distress when compared to the controls. Buprenorphine did not alter the progression of autoimmune disease, based on characteristics of splenic architecture and splenocyte cell profiles, development of lymphadenopathy, or kidney histology as compared to controls. This study indicates that buprenorphine at this dose and route of administration was ineffective in reducing distress associated with disease progression in the MRL/lpr strain. More studies are needed to determine if, at a different dose or route, buprenorphine would be useful as adjunctive therapy in reducing distress in MRL/lpr mice.

The notion of "immune privilege" in the central nervous system (CNS) has worked to perpetuate the impression that interactions between the brain and immune system are inherently detrimental. However the view of the CNS as an ivory tower, insulated from the reach and influence of the immune system, has been considerably challenged in recent years. Indeed, many of the immune processes thought to be absent in the CNS have been observed in the meningeal structures that follow the contours, ventricles and vasculature of the brain parenchyma. A large portion of this thesis is dedicated to T cell behavior in the meninges, which in spite of its profound influence on brain processes, immune surveillance, and neuropathology, remains poorly understood. Part of the original work herein attempts to elucidate the dynamics and the antigenic specificity of T cells within the meningeal space. By employing a parabiotic system of shared circulation we show that the CD4 turnover in the meninges to be slow relative to other tissues, dependent on a memory phenotype, and tightly coupled to the meninges draining deep cervical lymph node. As our perception of absolute immune privilege has changed, so have our view on the outcomes of T cell-CNS crosstalk. Whereas neuroimmunology was once nearly synonymous with immunemediated neuropathology, it now encompasses the emerging homeostatic roles of T cell-CNS interactions, including: hippocampal-dependent learning, stress response paradigms, and models of neurogenesis, neurodegeneration, and CNS injury. This body of work aims to shed light on the observation that lymphopenic mice exhibit significant behavioral impairment in spatial learning and memory tasks. Employing several transgenic mouse models in combination with adoptive transfers, we evidence the necessity of an antigen-specific CD4 T cell compartment in normal special learning and memory in mice. Specifically we show that lymphopenic mice manifest with an impaired spatial learning and memory phenotype that can be rescued by adoptive transfer of wild-type CD4 T cells. We go on to show that a monoclonal T cell population

Itch: its complex neurobiology, its exquisite evolutionary conservation, and even the undeniably euphoric sensation of the scratch it evokes, are all suggestive of a productive physiological function. Nevertheless, we still struggle to answer (or altogether overlook) the basic question of why we itch in the first place. Here, we propose a simple hypothesis: the purpose of itch sensation is to evoke scratching behavior, which in turn boosts protective immunity against the broad range of pathogenic challenges that enter at the skin. We propose that the key function of itch induced scratching is to physically disrupt the skin, serving as a "mechanical adjuvant" that amplifies and directs immune responses to the precise site of potential pathogen entry. As proof of principle, we show that the potent adjuvanticity of itch inducing Compound 48/80 is dependent on this agent's ability to elicit scratching behavior.