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Danyvid Olivares-Villagómez^*,, Yijie Wang^*, and Juan J. Lafaille^*

From the ^* Division of Molecular Pathogenesis, Skirball Institute of Biomolecular Medicine, and the Department of Pathology, and the 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, / T cell–deficient, or major histocompatibility complex class I–deficient mice did not develop EAE spontaneously, T/R⁺ mice crossed with TCR- 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- 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 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

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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