To analyze mechanisms governing tolerance and autoimmunity to self-antigens, we have generated lineages of transgenic mice that express the influenza virus PR8 hemagglutinin (HA) as a neo-self-antigen. By comparing the HA-specific T and B cell responses that can be induced in HA Tg mice with those that are induced in non-Tg (BALB/c) mice, the specificity and genetic basis with which tolerance is induced to the HA has been examined. This article summarizes studies using lineages of HA Tg mice that express different forms and amounts of the HA under the control of the SV40 promoter/enhancer. Our studies have revealed that specific subsets of HA-specific T and B cells are negatively selected from the primary repertoires of HA Tg mice. However, substantial populations of HA-specific T and B cells evade negative selection and can be activated by virus immunization. Understanding the capacity of these autoreactive lymphocytes to differentiate and participate in antigen-specific immune responses will provide important insights into mechanisms by which autoimmunity might be induced by viruses bearing structural similarities with self-antigens.