Activation-mediated CD4+ T cell unresponsiveness during acute Toxoplasma gondii infection in mice

Infection of mice with Toxoplasma gondii has been shown to induce a transient state of immune down-regulation. Earlier reports have demonstrated the role of cytokines, in particular IL-10, in this host response. Here evidence is presented that T. gondii, a major opportunistic pathogen of the newborn and those with AIDS, is able to induce CD4(+) T cell apoptosis in the infected murine host. We have examined the changes in the CD4(+) T cell population that occur during acute infection in an experimental mouse model. Seventy-six percent of the CD4(+) T cell population increased in volume by day 7 post-infection and expressed T cell maturation markers (CD44(hi), IL-2Rhi, Mel-14(lo)). Further noted was a clonal activation of several CD4(+) T cell to mitogen or parasite antigen stimulation was observed, in particular Vbeta5 T cells. Addition of rIL-2 partially restored the CD4(+) T cell proliferative response in vitro. The T cell activation marker CTLA-4 could not be detected and the co-stimulatory molecule, CD28, was down-regulated. Electrophoretic and morphologic analysis of these cells post-culture demonstrated a DNA fragmentation pattern and cell death consistent with apoptosis. These studies demonstrate for the first time in a protozoan parasite that activation induced CD4(+) T cell unresponsiveness occurs during acute T. gondii infection in mice, and may be important in immune down-regulation and parasite persistence in the infected host.