Down-regulation of host immune response to Toxoplasma gondii is associated with the expression of specific cytokines, in particular IL-10, and the induction of CD4+ T cell anergy. In the present study we report that the expression of both CD4 and CD2 antigen is down-regulated during the acute phase of infection. A decrease in the expression of CD2 was apparent during the acute phase of T. gondii infection in three genetically distinct strains of mice, CBA/J, C57BL/6, and BALB/c. The lymphoproliferative response induced by cross-linked anti-CD3 mAb or by Con A was markedly depressed. This suppressed response was associated with a reduction in the influx of Ca2+. We have examined whether lymphocytes from T. gondii mice maintain NF-AT transcription factors in the nucleus where they participate in the Ca2+-dependent induction of genes required for lymphocyte activation and proliferation. Immunofluorescence with confocal microscopy using an Ab to NF-ATc demonstrates a decrease in translocation of NF-ATc in T lymphocytes from acutely infected mice. Together, these results suggest that the defect in T cell expansion that occurs during acute murine toxoplasmosis is related to reduced activity of NF-AT, a calcium-dependent transcription factor required for T cell proliferation.