AbstractThelprgene has recently been shown to encode a functional mutation in the Fas receptor, a molecule involved in transducing apoptotic signals. Mice homozygous for thelprgene develop an autoimmune syndrome accompanied by massive accumulation of double‐negative (DN) CD4−8−B220+T cell receptor‐α/β+cells. In order to investigate the origin of these DN T cells, we derivedlpr/lprmice lacking major histocompatibility complex (MHC) class I molecules by intercrossing them with β2‐microglobulin (β2m)‐deficient mice. Interestingly, theselprβ2m–/– mice develop 13‐fold fewer DN T cells in lymph nodes as compared tolpr/lprwild‐type (lprWT) mice. Analysis of anti‐DNA antibodies and rheumatoid factor in serum demonstrates thatlprβ2m–/– mice produce comparable levels of autoantibodies tolprWT mice. Collectively our data indicate that MHC class I molecules control the development of DN T cells but not autoantibody production inIpr/lprmice and support the hypothesis that the majority of DN T cells may be derive