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 au toimmunity characterized by high titers of autoantibodies, lymphadenop athy, autoreactive T cells, and early mortality. The mechanism of auto immunity, however, remains unknown. The driving force for disease coul d result from the T cell recognition of autoantigen or, alternatively, an intrinsic T cell defect that promotes autoreactivity, We investiga ted the role of antigen-TCR interaction in the pathogenesis of lpr aut oimmunity by transferring the DO-11.10 TCR beta-chain transgene (V bet a 8.2-D beta 1.1-J beta 1.1) to the MRL-lpr/lpr background producing t he MRL-lpr beta strain. Our results show that the MRL-lpr beta transge nic strain has increased survival, lower titers of autoantibodies, and decreased lymphadenopathy compared with nontransgenic littermates. Th ese beneficial effects were associated with decreased expansion of CD4 (+) T cells expressing memory phenotypes (CD44(+), CD45RB(-), and LECA M(-)) in the transgenic compared with nontransgenic strains. A role fo r impaired recognition of autoantigen by T cells expressing the TCR tr ansgene was suggested by comparing the phenotypes of V beta 8.2(+) (tr ansgene(+)) vs V beta 8.2(-) (transgene(-)) CD4(+) T cells within the transgenic mice. These experiments show that V beta 8.2(-) T cells, wh ich 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.2() and V beta 8.2(-) subsets of nontransgenic mice. Based on these resu lts, we hypothesize that TCR recognition of autoantigen is a major con tributor to autoimmunity in lpr mice and that T cells expressing a mem ory phenotype are perpetrators of this process.