Parasite Fate and Involvement of Infected Cells in the Induction of CD4+ and CD8+ T Cell Responses to Toxoplasma gondii

Abstract

During infection with the intracellular parasite Toxoplasma gondii, the presentation of parasite-derived antigens to CD4+ and CD8+ T cells is essential for long-term resistance to this pathogen. Fundamental questions remain regarding the roles of phagocytosis and active invasion in the events that lead to the processing and presentation of parasite antigens. To understand the most proximal events in this process, an attenuated non-replicating strain of T. gondii (the cpsII strain) was combined with a cytometry-based approach to distinguish active invasion from phagocytic uptake. In vivo studies revealed that T. gondii disproportionately infected dendritic cells and macrophages, and that infected dendritic cells and macrophages displayed an activated phenotype characterized by enhanced levels of CD86 compared to cells that had phagocytosed the parasite, thus suggesting a role for these cells in priming naïve T cells. Indeed, dendritic cells were required for optimal CD4+ and CD8+ T cell responses, and the phagocytosis of heat-killed or invasion-blocked parasites was not sufficient to induce T cell responses. Rather, the selective transfer of cpsII-infected dendritic cells or macrophages (but not those that had phagocytosed the parasite) to naïve mice potently induced CD4+ and CD8+ T cell responses, and conferred protection against challenge with virulent T. gondii. Collectively, these results point toward a critical role for actively infected host cells in initiating T. gondii-specific CD4+ and CD8+ T cell responses.

Nonreplicating, Cyst-Defective Type II Toxoplasma gondii Vaccine Strains Stimulate Protective Immunity against Acute and Chronic Infection

“…Furthermore, phagocytosis of CPS by myeloid cells elicited surprisingly insignificant CD4 ϩ and CD8 ϩ T cell responses and ineffective immunity to Toxoplasma (21). In contrast, active invasion of myeloid cells by CPS triggered potent CD4 ϩ and CD8 ϩ T cell responses and highly effective protective immunity to Toxoplasma (21).…”

“…Recent studies using the CPS vaccination model have found a role for active parasite invasion in the activation of myeloid cells and the priming of CD4 ϩ and CD8 ϩ T cell immunity (30)(31)(32). Furthermore, phagocytosis of CPS by myeloid cells elicited surprisingly insignificant CD4 ϩ and CD8 ϩ T cell responses and ineffective immunity to Toxoplasma (21). In contrast, active invasion of myeloid cells by CPS triggered potent CD4 ϩ and CD8 ϩ T cell responses and highly effective protective immunity to Toxoplasma (21).…”

“…Disruption of the orotidine 5=-monophosphate decarboxylase gene (OMPDC) in the virulent type I RH ⌬ku80 strain (17) also produced a nonreplicating uracil auxotroph mutant that elicited protective immunity to virulent acute infection (18). The extreme attenuation and avirulence of type I T. gondii uracil auxotrophs are exemplified by survival of severely immune-deficient IFN-␥ Ϫ/Ϫ knockout mice (15, 18, 19) and interleukin-2 receptor ␥ knockout (NOD/SCID/IL-2R␥ Ϫ/Ϫ ) mice (20) that were infected with high-dose challenges of CPS.Vaccination with CPS elicits a lifelong CD8 ϩ T cell-dependent immunity against infection with type I strains (15,18,19,21,22 ϩ T cell responses and highly effective protective immunity to Toxoplasma (21).Previously, vaccination with CPS was shown to protect mice against a virulent acute infection after challenge with a type I or type II strain of T. gondii. However, this CPS vaccination did not completely prevent the development of cysts and chronic infection in mice that were challenged with a type II strain (33).…”

“…Vaccination with CPS elicits a lifelong CD8 ϩ T cell-dependent immunity against infection with type I strains (15,18,19,21,22 ϩ T cell responses and highly effective protective immunity to Toxoplasma (21).…”

Ly6Chigh Monocytes Control Cerebral Toxoplasmosis

“…Despite limited access, the CNS is inundated by immune cells from the periphery during the chronic stage of T. gondii infection. The adaptive immune responses in the CNS have been extensively investigated, describing an important contribution to the local parasite control (22)(23)(24)(25). Besides, several studies have highlighted the function and phenotype of certain mononuclear cells such as microglia, brain DCs, and macrophages upon cerebral toxoplasmosis; however, the role of recruited newly described myeloid cell subpopulations remains undefined (19,26,27).…”