The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/11/1883/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 10, November 16, 1998 1883-1894


Articles

Regulatory CD4+ T Cells Expressing Endogenous T Cell Receptor Chains Protect Myelin Basic Protein–specific Transgenic Mice from Spontaneous Autoimmune Encephalomyelitis

Danyvid Olivares-Villagómez*,{ddagger}, Yijie Wang*, and Juan J. Lafaille*

From the * Division of Molecular Pathogenesis, Skirball Institute of Biomolecular Medicine, and the Department of Pathology, and the {ddagger} Sackler Institute of Graduate Biomedical Sciences, New York University Medical Center, New York 10016

The development of T cell–mediated autoimmune diseases hinges on the balance between effector and regulatory mechanisms. Using two transgenic mouse lines expressing identical myelin basic protein (MBP)–specific T cell receptor (TCR) genes, we have previously shown that mice bearing exclusively MBP-specific T cells (designated T/R) spontaneously develop experimental autoimmune encephalomyelitis (EAE), whereas mice bearing MBP-specific T cells as well as other lymphocytes (designated T/R+) did not. Here we demonstrate that T/R mice can be protected from EAE by the early transfer of total splenocytes or purified CD4+ T cells from normal donors. Moreover, whereas T/R+ mice crossed with B cell–deficient, {gamma}/{delta} T cell–deficient, or major histocompatibility complex class I–deficient mice did not develop EAE spontaneously, T/R+ mice crossed with TCR-{alpha} and -β knockout mice developed EAE with the same incidence and severity as T/R mice. In addition, MBP-specific transgenic mice that lack only endogenous TCR-{alpha} chains developed EAE with high incidence but reduced severity. Surprisingly, two-thirds of MBP-specific transgenic mice lacking only endogenous TCR-β chains also developed EAE, suggesting that in T/R+ mice, cells with high protective activity escape TCR-β chain allelic exclusion. Our study identifies CD4+ T cells bearing endogenous {alpha} and β TCR chains as the lymphocytes that prevent spontaneous EAE in T/R+ mice.

Key Words: T helper cells • T cell receptor rearrangements • allelic exclusion • allelic inclusion • autorreactivity


Address correspondence to Juan J. Lafaille, Division of Molecular Pathogenesis, Skirball Institute of Biomolecular Medicine, New York University Medical Center, 550 First Ave., New York, NY 10016. Phone: 212-263-1489; Fax: 212-263-5711; E-mail: lafaille{at}saturn.med.nyu.edu

This work was partially supported by the National Institutes of Health (R21 and R01 AI41647), the Hirschl-Caulier Trust, and the Bernard B. Levine Investigatorship in Allergy and Immunology (J.J. Lafaille).

Abbreviations used: β2m, β2-microglobulin; EAE, experimental autoimmune encephalomyelitis; KO, knockout; MBP, myelin basic protein; RAG-1, recombination activating gene-1; T/R, MBP-specific T cell receptor transgenic mice with mutated RAG-1 genes; T/R+, MBP-specific T cell receptor transgenic mice with at least a normal RAG-1 gene.


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