Autoreactive T cells with atypical MHC restriction from MRL-lpr/lpr mice: Forbidden clones revisited

Abstract

MRL-lpr/lpr mice spontaneously develop a lethal form of systemic lupus erythematosus associated with massive lymphodenopathy, polyclonal B-cell activity, autoantibody production and antibody-dependent tissue injury. The sequence of events leading to B-cell proliferation and pathogenic autoantibody production are not clearly defined - abnormalities of both B and T cells have been observed. Isolation of individual T-cell clones would facilitate analysis of the cellular events involving both B and T cells that lead to autoantibody production. For this purpose, an autoreactive T-cell line (ARTC-1) was derived from the splenocytes of an unimmunized MRL-lpr/lpr mouse and maintained in culture by stimulation with syngeneic antigen presenting cells, without exogenous antigens. By T-cell receptor analysis it was demonstrated that ARC-1 cells developed as a clone even though no attempt was made to clone them in vitro: Southern blot analysis of ARTC-1 revealed a single rearrangement of the TcR β chain locus with the other TcR β chain gene remaining in the germline configuration. Northern blot analysis confirmed these findings and demonstrated that ARTC-1 utilized C(β)1 J(β) 1.3 exclusively. ARTC-1 had atypical MHC requirements for activation: antigen-presenting cells bearing both I-A(k) and I-E(k) major histocompatibility complex class II antigens were required for maximal proliferation of the ARTC-1 clone. Activated ARTC-l secreted solbule factors that induced B-cell proliferation, immunoglobulin secretion, and anti-DNA antibody production. Unregulated cells of the AR-TC1 type could, therefore, lead to polyclonal B-cell activation and autoantibody production in vivo in the absence of exogeneous antigenic stimulation.