Restriction of the TCR repertoire inhibits the development of memory T cells and prevents autoimmunity in lpr mice.
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.
Perkins
D L
DL
Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Listman
J A
JA
Marshak-Rothstein
A
A
Kozlow
W
W
Kelley
V R
VR
Finn
P W
PW
Rimm
I J
IJ
D000367:Age Factors; D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000517:prevention & control; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D015329:Gene Rearrangement, T-Lymphocyte; D007156:Immunologic Memory; D016131:Lymphocyte Subsets / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D012217:Rheumatoid Factor / Q000096:biosynthesis; D016019:Survival Analysis
D016693:Receptors, Antigen, T-Cell, alpha-beta; D012217:Rheumatoid Factor