Autoreactive T cells with atypical MHC restriction from MRL-lpr/lpr mice: forbidden clones revisited.
MRL-lpr/lpr mice spontaneously develop a lethal form of systemic lupus erythematosus associated with massive lymphadenopathy, 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 ARTC-1 cells developed as a clone even through no attempt was made to clone them in vitro: Southern blot analysis of ARTC-1 revealed a single rearrangement of the TcR beta chain locus with the other TcR beta chain gene remaining in the germline configuration. Northern blot analysis confirmed these findings and demonstrated that ARTC-1 utilized C beta 1 J beta 1.3 exclusively. ARTC-1 had atypical MHC requirements for activation: antigen-presenting cells bearing both I-Ak and I-Ek major histocompatibility complex class II antigens were required for maximal proliferation of the ARTC-l clone. Activated ARTC-l secreted soluble 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 exogenous antigenic stimulation.
Naparstek
Y
Y
Department of Medicine, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts 02111.
Baur
K
K
Reis
M D
MD
Breitman
L
L
Mak
T W
TW
Schwartz
R S
RS
Madaio
M P
MP
D000818:Animals; D000917:Antibody Formation; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology; D002455:Cell Division; D002460:Cell Line / Q000276:immunology; D002999:Clone Cells / Q000276:immunology; D000939:Epitopes; D015333:Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics; D008285:Major Histocompatibility Complex; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics*; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000276:immunology*
D001323:Autoantibodies; D000939:Epitopes; D000949:Histocompatibility Antigens Class II