Infection of C57BL/6 mice with Mycobacterium avium leads to the activation of both CD4 + and CD8 + gamma interferon (IFN-γ)-producing T cells, although the CD8 + cells play no role in protection against infection. Using transfer of different lines of transgenic T cells with T-cell receptors (TCRs) which recognize irrelevant antigens, we show here that transferred CD8 + T cells from two of the three lines were activated to the same degree as the host cells, suggesting that the majority of the IFN-γ-producing CD8 + T cells of the host represented bystander activation. The third line, specific for the male HY antigen, showed no activation. Activation required the participation of the CD28 coreceptor on T cells and was unaffected by the removal of CD44 hi (memory phenotype) T cells. The transferred CD8 + T cells proliferated in vivo, although this was not essential for IFN-γ production. Taken together, these data are highly reminiscent of homeostatic proliferation of TCR transgenic T cells upon transfer to lymphopenic hosts, and suggest low-affinity stimulation through the TCR, possibly by self peptides. The findings are discussed in relation to homeostatic proliferation and their significance in the possible induction of autoimmune disease.