Brain antigen-reactive CD4+ T cells are sufficient to support learning behavior in mice with limited T cell repertoire.

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.

Clinical efficacy of buprenorphine to minimize distress in MRL/lpr mice.

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.

MHCII-independent CD4+ T cells protect injured CNS neurons via IL-4.

A body of experimental evidence suggests that T cells mediate neuroprotection following CNS injury; however, the antigen specificity of these T cells and how they mediate neuroprotection are unknown. Here, we have provided evidence that T cell-mediated neuroprotection after CNS injury can occur independently of major histocompatibility class II (MHCII) signaling to T cell receptors (TCRs). Using two murine models of CNS injury, we determined that damage-associated molecular mediators that originate from injured CNS tissue induce a population of neuroprotective, IL-4-producing T cells in an antigen-independent fashion. Compared with wild-type mice, IL-4-deficient animals had decreased functional recovery following CNS injury; however, transfer of CD4+ T cells from wild-type mice, but not from IL-4-deficient mice, enhanced neuronal survival. Using a culture-based system, we determined that T cell-derived IL-4 protects and induces recovery of injured neurons by activation of neuronal IL-4 receptors, which potentiated neurotrophin signaling via the AKT and MAPK pathways. Together, these findings demonstrate that damage-associated molecules from the injured CNS induce a neuroprotective T cell response that is independent of MHCII/TCR interactions and is MyD88 dependent. Moreover, our results indicate that IL-4 mediates neuroprotection and recovery of the injured CNS and suggest that strategies to enhance IL-4-producing CD4+ T cells have potential to attenuate axonal damage in the course of CNS injury in trauma, inflammation, or neurodegeneration.