HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Liu, J. Articles by Gendelman, H. E. Search for Related Content PubMed PubMed Citation Articles by Liu, J. Articles by Gendelman, H. E.

Neuromodulatory Activities of CD4⁺CD25⁺ Regulatory T Cells in a Murine Model of HIV-1-Associated Neurodegeneration¹

Center for Neurovirology and Neurodegenerative Disorders and Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198

HIV-1-associated neurocognitive impairments are intrinsically linked to microglial immune activation, persistent viral infection, and inflammation. In the era of antiretroviral therapy, more subtle cognitive impairments occur without adaptive immune compromise. We posit that adaptive immunity is neuroprotective, serving in both the elimination of infected cells through CD8⁺ cytotoxic T cell activities and the regulation of neuroinflammatory responses of activated microglia. For the latter, little is known. Thus, we studied the neuromodulatory effects of CD4⁺ regulatory T cells (Treg; CD4⁺CD25⁺) or effector T cells in HIV-1-associated neurodegeneration. A newly developed HIV-1 encephalitis mouse model was used wherein murine bone marrow-derived macrophages are infected with a full-length HIV-1_YU2/vesicular stomatitis viral pseudotype and injected into basal ganglia of syngeneic immunocompetent mice. Adoptive transfer of CD3-activated Treg attenuated astrogliosis and microglia inflammation with concomitant neuroprotection. Moreover, Treg-mediated anti-inflammatory activities and neuroprotection were associated with up-regulation of brain-derived neurotrophic factor and glial cell-derived neurotrophic factor expression and down-regulation of proinflammatory cytokines, oxidative stress, and viral replication. Effector T cells showed contrary effects. These results, taken together, demonstrate the importance of Treg in disease control and raise the possibility of their utility for therapeutic strategies.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants 2R01 NS034239, 2R37 NS36126, P01 NS31492, P20RR 15635, P01MH64570, and P01 NS43985 (to H.E.G.).

² Address correspondence and reprint requests to Dr. Howard E. Gendelman, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985880 Nebraska Medical Center, Omaha, NE 68198-5880. E-mail address: hegendel{at}unmc.edu

³ Abbreviations used in this paper: HAND, HIV-1-associated neurocognitive disorder; BDNF, brain-derived neurotrophic factor; BMM, bone marrow-derived macrophage; CM, conditioned medium; DAPI, 4',6'-diamidino-2-phenylindole; FOXP3, Forkhead box P3; GDNF, glial cell line-derived neurotrophic factor; GFAP, glial fibrillary acidic protein; HIVE, HIV encephalitis; i.c., intracerebral; MAP, microtubule-associated protein; MP, mononuclear phagocyte; NeuN, neuronal nuclei protein; ROS, reactive oxygen species; Teff, effector T cell; Treg, regulatory T cell; VSV, vesicular stomatitis virus; M-CSF, macrophage CSF.