Restriction of the TCR repertoire inhibits the development of memory T cells and prevents autoimmunity in lpr mice
Perkins, D.L.; Listman, J.A.; Marshak-Rothstein, A.; Kozlow, W.; Kelley, V.R.; Finn, P.W.; Rimm, I.J.
Journal of Immunology 156(12): 4961-4968
1996
ISSN/ISBN: 0022-1767 PMID: 8648148 Document Number: 457737
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 (V-beta-8.2-D-beta-1.1-J-beta-1.1) to the MRL-lpr/lpr background producing the MRL-lpr-beta 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 V-beta-8.2+ (transgene+) vs V-beta-8.2- (transgene-) CD4+ T cells within the transgenic mice. These experiments show that V-beta-8.2- 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 V-beta-8.2+ and V-beta-8.2- 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.