Increased susceptibility of Fas ligand-deficientgld mice toTrypanosoma cruzi infection due to a Th2-biased host immune response

Abstract

Infection of BALB/c mice with Trypanosoma cruzi resulted in up-regulated expression of Fas and Fas ligand (FasL) mRNA by splenic CD4 + T cells, activation-induced CD4 + T cell death (AICD), and in Fas : FasL-mediated cytotoxicity. When CD4 + T cells from infected mice were co-cultured with T. cruzi-infected macrophages, onset of AICD exacerbated parasite replica-tion. CD4 + T cells from T. cruzi-infected FasL-deficient BALB gld/gld mice had no detectable AICD in vitro and their activation with anti-TCR did not exacerbate T. cruzi replication in mac-rophages. However, infection of BALB gld/gld mice with T. cruzi resulted in higher and more prolonged parasitemia, compared to wild-type mice. Secretion of Th2 cytokines IL-10 and IL-4 by CD4 + T cells from infected gld mice was markedly increased, compared to controls. In addition, in vivo injection of anti-IL-4 mAb, but not of an isotype control mAb, reduced parasitemia in both gld and wild-type mice. These results indicate that, besides controlling CD4 + T cell AICD and parasite replication in vitro, an intact Fas : FasL pathway also controls the host cytokine response to T. cruzi infection in vivo, being required to prevent an exacerbated Th2-type immune response to the parasite.

Death of adrenocortical cells during murine acute T. cruzi infection is not associated with TNF-R1 signaling but mostly with the type II pathway of Fas-mediated apoptosis

“…As regards to T. cruzi infection, while Fas apoptotic pathway plays a role in the immune response regulation (Lopes et al, 1999), the Fas/Fas-L signaling is also implicated in the induction of peripheral lymphocyte death, atrophy of mesenteric lymph nodes and the myocardial damage, but does not seem quite involved in thymic atrophy (De Souza et al, 2003;Guillermo et al, 2007;Rodrigues Jr. et al, 2007). As regards endocrine tissue Fas is expressed in all zones of adrenal glands (Leithäuser et al, 1993), but it is unknown whether the adrenal Fas/Fas-L cascade plays a role during T. cruzi infection.…”

Modulation of Host Cell Apoptosis byTrypanosoma cruzi: Repercussions in the Development of Chronic Chagasic Cardiomyopathy

“…This has been complemented by the observation of a higher percentage of apoptotic cells in the hearts of patients with cardiac damage as compared with asymptomatic patients. Experimental evidence shows that the induction of apoptosis in CD4 + T cells occurs through the induction of Fas/ FasL and the activation of the executioner caspases 3 and 8 [103]. The participation of Fas/Fas-L was verified by in vivo injection of anti-FasL antibodies, which blocked the induced apoptosis of CD8 + T lymphocytes, improving the Th1 response against the parasite.…”

Immunopathogenesis in Trypanosoma cruzi infection: a role for suppressed macrophages and apoptotic cells

“…The antagonist anti-FasL mAb ( 62 ), the caspase-8 inhibitor zIETD, and the pan caspase inhibitor zVAD ( 60 , 61 ) prevent activation-induced death in T cells from infected mice. T cell proliferation increases in the presence of anti-FasL and in T cells from infected FasL-deficient gld mutant mice ( 59 , 62 ). These findings indicate that Fas-mediated apoptosis might counteract T cell expansion during infection.…”

“…During acute infection, antigen-specific effector CD8 T cells from infected mice express Fas and a proapoptotic phenotype ( 63 ). Likewise, CD4 T cells undergo Fas-mediated apoptosis and express a reduced ability to help infected macrophages ( 41 , 59 ). The use of anti-FasL or CD4 T cells from infected gld mice allowed macrophages to control intracellular infection ( 41 , 59 ).…”