Apoptotic CD8 T-lymphocytes disable macrophage-mediated immunity to Trypanosoma cruzi infection

Abstract

Chagas disease is caused by infection with the protozoan Trypanosoma cruzi. CD8 T-lymphocytes help to control infection, but apoptosis of CD8 T cells disrupts immunity and efferocytosis can enhance parasite infection within macrophages. Here, we investigate how apoptosis of activated CD8 T cells affects M1 and M2 macrophage phenotypes. First, we found that CD8 T-lymphocytes and inflammatory monocytes/macrophages infiltrate peritoneum during acute T. cruzi infection. We show that treatment with anti-Fas ligand (FasL) prevents lymphocyte apoptosis, upregulates type-1 responses to parasite antigens, and reduces infection in macrophages cocultured with activated CD8 T cells. Anti-FasL skews mixed M1/M2 macrophage profiles into polarized M1 phenotype, both in vitro and following injection in infected mice. Moreover, inhibition of T-cell apoptosis induces a broad reprogramming of cytokine responses and improves macrophage-mediated immunity to T. cruzi. The results indicate that disposal of apoptotic CD8 T cells increases M2-macrophage differentiation and contributes to parasite persistence.

Distinct Trypanosoma cruzi isolates induce activation and apoptosis of human neutrophils

“…We found that neutrophils exposed to both isolates display higher percentage of apoptosis compared with non-infected ones. Interestingly, Freire-de-Lima and colleagues demonstrated that macrophages in contact with apoptotic cells favor the intracellular parasite growth and increase parasitemia [ 44 , 45 ]. More recently, it was demonstrated that apoptotic neutrophils increase T .…”

“…cruzi replication in macrophages. They also showed that blocking apoptosis through anti-FasL treatment can restrict parasite growth and increase NO production [ 45 ]. Our analysis also showed that the higher the intensity of CFSE expression, indicating interaction with a higher number of parasites, the higher the expression of cytokines and the occurrence of apoptosis.…”

Efferocytosis of Pathogen-Infected Cells

“…Mouse experiments support the concept that phagocyte uptake of apoptotic T lymphocytes results in the establishment of an anti-inflammatory response dictated by TGF-β and prostaglandin PGE2 that fuels parasite persistence and disease ( 126 ). Treatment of T. cruzi infected mice with inhibitors of apoptosis reversed the anti-inflammatory phenotype and reduced ex vivo parasite replication ( 123 , 127 ), consistent with efferocytosis of apoptotic cells reducing macrophage anti-parasite activity and enhancing parasite persistence and disease.…”

“…Trypanosma cruzi infection induces lymphocyte apoptosis in both experimentally infected mice ( 122 , 123 ) and infected humans ( 124 ), and disease severity correlated with the degree of ex vivo apoptosis observed ( 124 , 125 ). Mouse experiments support the concept that phagocyte uptake of apoptotic T lymphocytes results in the establishment of an anti-inflammatory response dictated by TGF-β and prostaglandin PGE2 that fuels parasite persistence and disease ( 126 ).…”

New Insights into the Immunobiology of Mononuclear Phagocytic Cells and Their Relevance to the Pathogenesis of Cardiovascular Diseases

“…TGF-β promotes in macrophages the L -arginine metabolism by arginase to synthesize polyamines which functions as a growth factor for parasites ( 66 ). Another work found that blocking apoptosis of CD8 + T cells in cocultures, infected macrophages increase NO levels and M1 features leading to restrict intracellular parasite growth ( 67 ). In addition, while coculture of apoptotic neutrophils induce an M2-like phenotype in infected macrophages, live neutrophils via elastase induce M1 macrophages with NO and TNF production that allow to control T. cruzi replication ( 68 ).…”