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The Journal of Neuroscience, May 5, 2004, 24(18):4333-4339; doi:10.1523/JNEUROSCI.5276-03.2004

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Development/Plasticity/Repair
CD4-Positive T Cell-Mediated Neuroprotection Requires Dual Compartment Antigen Presentation

Susanna C. Byram,^1,2 Monica J. Carson,³ Cynthia A. DeBoy,^1,2 Craig J. Serpe,² Virginia M. Sanders,⁴ and Kathryn J. Jones^1,2

¹Department of Cell Biology, Neurobiology, and Anatomy, Loyola University Chicago, Maywood, Illinois 60153, ²Research and Development Service, Hines Veterans Affairs Hospital, Hines, Illinois 60141, ³Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037, and ⁴Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University, Columbus, Ohio 43210

Our laboratory discovered that CD4-positive (CD4⁺) T cells of the immune system convey transitory neuroprotection to injured mouse facial motoneurons (FMNs) (Serpe et al., 1999, 2000, 2003). A fundamental question in the mechanisms responsible for neuroprotection concerns the identity of the cell(s) that serves as the antigen-presenting cell (APC) to activate the CD4⁺ T cells. Here, we first establish that CD4⁺ T cells reactive to non-CNS antigen fail to support FMN survival and, second, demonstrate a two-compartment model of CD4⁺ T cell activation. Mouse bone marrow (BM) chimeras were developed that discriminate between resident antigen-presenting host cell and BM-derived antigen-presenting donor cell expression of major histocompatibility complex II within central and peripheral compartments, respectively. After facial nerve transection, neither compartment alone is sufficient to result in activated CD4⁺ T cell-mediated FMN survival. Rather, CD4⁺ T cell-mediated neuroprotection appears to depend on both resident microglial cells in the central compartment and a BM-derived APC in the peripheral compartment. This is the first in vivo report demonstrating a neuroprotective mechanism requiring APC functions by resident (i.e., parenchymal) microglial cells.

Key words: microglia; chimera mice; antigen-presenting cell; motoneuron survival; CD4⁺ T lymphocytes; neuro-immune interactions; facial motoneuron

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Received Nov 29, 2003; revised March 23, 2004; accepted March 24, 2004.

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