Endogenous presentation of self myelin epitopes by CNS-resident APCs in Theiler’s virus–infected mice
Yael Katz-Levy, … , Lit Jen Tan, Stephen D. Miller
Yael Katz-Levy, … , Lit Jen Tan, Stephen D. Miller
Published September 1, 1999
Citation Information: J Clin Invest. 1999;104(5):599-610. https://doi.org/10.1172/JCI7292.
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Article

Endogenous presentation of self myelin epitopes by CNS-resident APCs in Theiler’s virus–infected mice

Abstract

The mechanisms underlying the initiation of virus-induced autoimmune disease are not well understood. Theiler’s murine encephalomyelitis virus–induced demyelinating disease (TMEV-IDD), a mouse model of multiple sclerosis, is initiated by TMEV-specific CD4+ T cells targeting virally infected central nervous system–resident (CNS-resident) antigen-presenting cells (APCs), leading to chronic activation of myelin epitope–specific CD4+ T cells via epitope spreading. Here we show that F4/80+, I-As+, CD45+ macrophages/microglia isolated from the CNS of TMEV-infected SJL mice have the ability to endogenously process and present virus epitopes at both acute and chronic stages of the disease. Relevant to the initiation of virus-induced autoimmune disease, only CNS APCs isolated from TMEV-infected mice with preexisting myelin damage, not those isolated from naive mice or mice with acute disease, were able to endogenously present a variety of proteolipid protein epitopes to specific Th1 lines. These results offer a mechanism by which localized virus-induced, T cell–mediated inflammatory myelin destruction leads to the recruitment/activation of CNS-resident APCs that can process and present endogenous self epitopes to autoantigen-specific T cells, and thus provide a mechanistic basis by which epitope spreading occurs.

Authors

Yael Katz-Levy, Katherine L. Neville, Ann M. Girvin, Carol L. Vanderlugt, Jonathan G. Pope, Lit Jen Tan, Stephen D. Miller

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Viral, but not myelin, epitopes are endogenously presented by CNS-reside...
Viral, but not myelin, epitopes are endogenously presented by CNS-resident APCs isolated from SJL mice at the onset of TMEV-IDD. (a) A total of 1.8 × 104 plastic-adherent spinal cord mononuclear cells were prepared from SJL mice 42 days after intracerebral infection with TMEV. The CNS APCs were irradiated and cultured with either 3 × 104 sTV1 T cells (specific for VP2 70-86) or the same number of T cells from a long-term PLP139-151–specific line. T-cell lines cultured with 1.8 × 104 irradiated splenocytes + 50 μM of the appropriate peptide served as the positive control. (b) A total of 104 to 105 irradiated microglia isolated from the brains of naive SJL mice or irradiated naive splenocytes were cultured with 3 × 104 T cells from a long-term PLP139-151–specific line in the presence or absence of 50 μM of PLP139-151 or 25 μg/mL of the MP-4 MBP/PLP fusion protein. (c) A total of 104 to 105 irradiated microglia isolated from the brains of naive SJL mice or irradiated naive splenocytes were cultured with 3 × 104 cloned T-cell hybridoma cells specific for TMEV VP2 70-86 in the presence or absence of the peptide. For a and b, cultures were pulsed with 1 μCi of [3H]TdR at 48 hours, and were harvested 16–24 hours thereafter. For c, culture supernates were harvested after 48 hours and tested for their ability to support the proliferation of the IL-2–dependent CTLL-2 cell line. Values represent the mean cpm ± SEM of triplicate cultures. Stimulation indices are indicated above each bar.