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Immunodominance in the TCR Repertoire of TCR Peptide-Specific CD4⁺ Treg Population That Controls Experimental Autoimmune Encephalomyelitis¹

Loui Thomas Madakamutil^*, Igor Maricic^*,, Eli E. Sercarz^*, and Vipin Kumar^2,*,

^* Division of Immune Regulation, La Jolla Institute for Allergy and Immunology, San Diego, CA 92037; and Laboratories of Autoimmunity and Immune Regulation, Torrey Pines Institute for Molecular Studies, San Diego, CA 92121

Immunodominance in self-Ag-reactive pathogenic CD4⁺ T cells has been well established in several experimental models. Although it is clear that regulatory lymphocytes (Treg) play a crucial role in the control of autoreactive cells, it is still not clear whether immunodominant CD4⁺ Treg clones are also involved in control of autoreactivity. We have shown that TCR-peptide-reactive CD4⁺ and CD8⁺ Treg play an important role in the spontaneous recovery and resistance from reinduction of experimental autoimmune encephalomyelitis in B10.PL mice. We report, by sequencing of the TCR - and β-chain associated with CD4⁺ Treg, that the TCR repertoire is limited and the majority of CD4⁺ Treg use the TCR Vβ14 and V4 gene segments. Interestingly, sequencing and spectratyping data of cloned and polyclonal Treg populations revealed that a dominant public CD4⁺ Treg clonotype expressing Vβ14-Jβ1.2 with a CDR3 length of 7 aa exists in the naive peripheral repertoire and is expanded during the course of recovery from experimental autoimmune encephalomyelitis. Furthermore, a higher frequency of CD4⁺ Treg clones in the naive repertoire correlates with less severity and more rapid spontaneous recovery from disease in parental B10.PL or PL/J and (B10.PL x PL/J)F₁ mice. These findings suggest that unlike the Ag-nonspecific, diverse TCR repertoire among the CD25⁺CD4⁺ Treg population, TCR-peptide-reactive CD4⁺ Treg involved in negative feedback regulation of autoimmunity use a highly limited TCR V-gene repertoire. Thus, a selective set of immunodominant Treg as well as pathogenic T cell clones can be targeted for potential intervention in autoimmune disease conditions.

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 Grants from the National Institutes of Health, the National Multiple Sclerosis Society, and the Multiple Sclerosis National Research Institute (to V.K.).

² Address correspondence and reprint requests to Dr. Vipin Kumar, Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA 92121. E-mail address: vkumar{at}tpims.org

³ Abbreviations used in this paper: MBP, myelin basic protein; EAE, experimental autoimmune encephalomyelitis; PTx, Pertussis toxin; RIS, relative index of stimulation.

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