Restriction of the TCR repertoire inhibits the development of memory T cells and prevents autoimmunity in lpr mice.

Abstract

The lpr mutation, a disruption of the fas gene, induces spontaneous autoimmunity characterized by high titers of autoantibodies, lymphadenopathy, autoreactive T cells, and early mortality. The mechanism of autoimmunity, however, remains unknown. The driving force for disease could result from the T cell recognition of autoantigen or, alternatively, an intrinsic T cell defect that promotes autoreactivity. We investigated the role of antigen-TCR interaction in the pathogenesis of lpr autoimmunity by transferring the DO-11.10 TCR beta-chain transgene (Vbeta8.2-Dbeta1.1-Jbeta1.1) to the MRL-lpr/lpr background producing the MRL-lprbeta strain. Our results show that the MRL-lpr beta transgenic strain has increased survival, lower titers of autoantibodies, and decreased lymphadenopathy compared with nontransgenic littermates. These beneficial effects were associated with decreased expansion of CD4+ T cells expressing memory phenotypes (CD44+, CD45RB-, and LECAM-) in the transgenic compared with nontransgenic strains. A role for impaired recognition of autoantigen by T cells expressing the TCR transgene was suggested by comparing the phenotypes of Vbeta8.2+ (transgene+) vs Vbeta8.2- (transgene-) CD4+ T cells within the transgenic mice. These experiments show that Vbeta8.2- T cells, which express endogenously rearranged TCR, are the major contributors to the expansion of memory T cells in the transgenic mice. In contrast, T cells with memory phenotypes expand similarly in both the Vbeta8.2+ and Vbeta8.2- subsets of nontransgenic mice. Based on these results, we hypothesize that TCR recognition of autoantigen is a major contributor to autoimmunity in lpr mice and that T cells expressing a memory phenotype are perpetrators of this process.

• Authors: D L Perkins, J A Listman, A Marshak-Rothstein, W Kozlow, V R Kelley, P W Finn, I J Rimm
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 156 Issue 12 Pg. 4961-8 (Jun 15 1996) ISSN: 0022-1767 [Print] United States
• PMID: 8648148 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Receptors, Antigen, T-Cell, alpha-beta
• Rheumatoid Factor

Topics

• Age Factors
• Animals
• Autoimmune Diseases (immunology, prevention & control)
• CD4-Positive T-Lymphocytes (immunology)
• Gene Rearrangement, T-Lymphocyte
• Immunologic Memory
• Lymphocyte Subsets (immunology)
• Mice
• Mice, Mutant Strains
• Mice, Transgenic
• Receptors, Antigen, T-Cell, alpha-beta (genetics)
• Rheumatoid Factor (biosynthesis)
• Survival Analysis