Apoptosis differentially regulates mesenteric and subcutaneous lymph node immune responses to Trypanosoma cruzi

Abstract

Infection with Trypanosoma cruzi causes expansion of subcutaneous (SLN) and atrophy of mesenteric (MLN) lymph nodes. Here we show that excision of MLN increased parasitemia in T. cruzi-infected mice. We then studied how apoptosis of MLN cells affects immune responses to infection. T cell apoptosis increased in the MLN compared to SLN in T. cruzi-infected mice. Absolute numbers of naïve T cells decreased, and activated T cells failed to accumulate in MLN during infection. In addition, activated T cells from MLN produced less IL-2, IFN-c, IL-4, and IL-10 than T cells from SLN. Treatment with IL-4 or with caspase-9 inhibitor increased the recovery of viable T cells in vitro. Treatment with caspase-9 inhibitor also increased the production of cytokines by MLN T cells from infected mice. Moreover, injection of a pan caspase inhibitor prevented MLN atrophy during T. cruzi infection. Caspase-9, but not caspase-8, inhibitor also reduced MLN atrophy and increased the recovery of naïve and activated T cells from MLN. These findings indicate that caspase-mediated apoptosis and defective cytokine production are implicated in MLN atrophy and affect immune responses to T. cruzi infection.

Apoptotic lymphocytes treated with IgG from Trypanosoma cruzi infection increase TNF‐α secretion and reduce parasite replication in macrophages

“…Infection with T. cruzi increases lymphocyte apoptosis [8][9][10][11][12], and systemic exposure to apoptotic cells elicits production of autoantibodies reactive with apoptotic cells [18]. Therefore, we investigated whether infection by T. cruzi elicits autoantibodies against apoptotic lymphocytes.…”

“…Infection with T. cruzi induces lymphocyte apoptosis [8][9][10][11][12], and the phagocytic clearance of apoptotic lymphocytes drives replication of T. cruzi in macrophages [13]. Parasite replication results from a biochemical cascade that originates from binding of apoptotic cells to a V b 3 integrin, followed by production of PGE 2 and TGF-b1, induction of ornithine decarboxylase and increased production of the polyamine putrescine [13].…”

The importance of apoptosis for immune regulation in Chagas disease

“…The key event in cell death signalling is the activation of caspases and the cleavage of target substrates. In order to understand whether the mechanisms of apoptosis involve the extrinsic or intrinsic pathways, we used inhibitors of caspase-8 and caspase-9 , de Meis et al 2008. One criticism is that the specificity of these inhibitors occurs only at low doses (Pereira & Song 2008).…”

Back to the future in Chagas disease: from animal models to patient cohort studies, progress in immunopathogenesis research

“…Another important inference derived from the above study was that long-term host exposure to T. cruzi does not lead to the exhaustion of the dominant T cell specificities, at least in the mouse model. Additional studies are required to determine if the depressed generation of T CM may reflect dysfunctions associated with parasitism of the thymus and/or secondary lymphoid tissues (De Meis et al 2008). …”