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

Abstract

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.

Macrophage and T lymphocyte apoptosis during experimental pulmonary tuberculosis: their relationship to mycobacterial virulence

“…It has been proposed that in several chronic infectious diseases, such as trypanosomiasis, toxoplasmosis, or schistosomiasis, immunopathology relates to selective apoptotic depletion of Th1 cells that are necessary for resolving the infection [23][24][25]. Th1 lymphocytes appear to be more susceptible than Th0 or Th2 cells to Fas-mediated apoptosis [11].…”

Apoptotic Deletion of Th Cells Specific for the 19-kDa Carboxyl-Terminal Fragment of Merozoite Surface Protein 1 During Malaria Infection

“…Activation-induced T cell death is responsible for exacerbation of Trypanosoma cruzi growth in macrophages (23). Toxoplasma gondii infection induces CD4 ϩ T cell apoptosis, and as a consequence, a transient state of unresponsiveness occurs (24). The mechanism and the factors responsible for malaria-induced apoptosis remain to be established.…”

Importance of CD8 T cell-mediated immune response during intracellular parasitic infections and its implications for the development of effective vaccines

“…The treatment with specific neutralizing monoclonal antibodies to mouse IFN-γ completely reversed the immunity mediated by these T cells in naïve mice (Khan et al 1994).…”

“…Finally, the importance of CD8 T cells was demonstrated by the adoptive transfer of T cell clones specific for a T. gondii antigen. αβ Tcell receptor+, CD4-and CD8+ T cells specific for the P30 (Sag1) antigen conferred a high degree of protective immunity against a lethal challenge with T. gondii (Khan et al 1994).…”

“…This result was confirmed by the immunization with native protein that elicited protective immunity dependent on the activation of this subpopulation of lymphocytes (Khan et al 1991). CD8 T cell clones specific for the purified P30 antigen (SAG1) were generated and, when adoptively transferred to naive mice, protected them against acute infection with T. gondii (Khan et al 1994).…”