We previously demonstrated that hematopoietic cell protein-tyrosine phosphatase (HCP) is one of the molecules which can transduce Fas-mediated apoptosis signals in lymphoid cells. The present study analyzed the effect of defective Fas signaling on the T cell phenotype and apoptosis function in 6week-old HCP-deficient motheaten mice. Viable motheaten (me'lme") mice exhibited increased T cell proliferation in the lymph node (LN), which was due to defective activation-induced apoptosis. There was also a defective elimination of Fas+ T cells in the LN of me'lme" mice, which was not ascribed to defective Fas expression or defective Fas ligand function. Although activated T cells from me'lme" mice expressed high levels of Fas, they were resistant to anti-Fas induced apoptosis. No protein tyrosine dephosphorylation signal was delivered after anti-Fas crosslinking in the T cells of me'lme" mice as revealed by 32Pt labeling of protein phosphatase substrates. The defective activation-induced apoptosis of Fas+ T cells was associated with lymphodenopathy as well as an increased number of population of CD4, CD8+, B220+. CD3+ T cells expressing upregulated levels of Fas in the LN of me'lme" mice. Pneumonitis in me'lme' mice was associated with infiltration of cycling T cells detected by bromodeoxyuridine (BrdU) uptake in vivo. Thus, T ceils from me'lme" mice are resistant to Fas-mediated apoptosis due to the defective apoptotic signaling, which is associated with abnormal maturation, proliferation and tissue infiltration.