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Enhanced Migratory Capacity of T Lymphocytes in Severe Chagasic Patients Is Correlated With VLA-4 and TNF-α
Luiz Ricardo Berbert1, Florencia Belén González2, Silvina Raquel Villar2
1Laboratory on Thymus Research, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.
Insights
Chagas disease myocarditis involves T cells migrating to the heart, driven by fibronectin and tumor necrosis factor-alpha (TNF-α). Enhanced expression of these molecules and their receptors promotes T cell accumulation in chronic Chagasic myocarditis (CCM) patients.
Area of Science:
- Immunology
- Cardiology
- Parasitology
Background:
- Chronic Chagas disease (CCM) involves T cell infiltration in heart tissue.
- T cell recruitment may be influenced by chemokines like CXCL12, cytokines like TNF-α, and extracellular matrix proteins like fibronectin.
- Understanding these molecular interactions is crucial for CCM pathogenesis.
Purpose of the Study:
- To investigate the expression of fibronectin, CXCL12, and TNF-α in the heart tissue of individuals with Chagas disease.
- To analyze T lymphocyte activation and migration markers in chronic Chagasic patients.
- To assess the migratory capacity of T cells and PBMCs from CCM patients in response to fibronectin and TNF-α.
Main Methods:
- Quantitative analysis of fibronectin, CXCL12, and TNF-α in myocardial tissue.
- Flow cytometry to measure HLA-DR and VLA-4 expression on T lymphocytes.
- Ex vivo migration assays using peripheral blood mononuclear cells (PBMCs) and T cells from CCM patients.
Main Results:
- CCM patients showed increased myocardial expression of fibronectin, CXCL12, and TNF-α.
- Serum levels of CXCL12 and TNF-α were elevated in CCM individuals.
- T lymphocytes from CCM patients exhibited higher expression of HLA-DR and VLA-4.
- PBMCs and T cells from CCM patients demonstrated enhanced migration in response to fibronectin, further increased by TNF-α.
Conclusions:
- Enhanced cardiac expression of fibronectin and TNF-α contributes to T cell recruitment in CCM.
- Increased VLA-4 expression on T cells facilitates their migration.
- These findings suggest a mechanism for activated T cell accumulation in the hearts of chronic Chagas disease patients.
Abstract:
Trypanosoma cruzi infection in humans leads to progression to chronic chagasic myocarditis (CCM) in 30% of infected individuals, paralleling T cell inflammatory infiltrates in the heart tissue. T-cell trafficking into the hearts of CCM patients may be modulated by in situ expression of chemotactic or haptotactic molecules, as the chemokine CXCL12, the cytokine tumor necrosis factor-alpha (TNF-α), and extracellular matrix proteins (ECM), such as fibronectin. Herein we evaluated the expression of fibronectin, CXCL12, and TNF-α in the myocardial tissue of T. cruzi seropositive (asymptomatic or with CCM), as well as seronegative individuals as healthy controls. Hearts from CCM patients exhibited enhanced expression of these three molecules. CXCL12 and TNF-α serum levels were also increased in CCM individuals. We then evaluated T lymphocytes from chronic chagasic patients by cytofluorometry, in terms of membrane expression levels of molecules involved in cell activation and cell migration, respectively, HLA-DR and the VLA-4 (very late antigen-4, being one integrin-type fibronectin receptor). Indeed, the expression of HLA-DR and VLA-4 was enhanced on T lymphocytes from chagasic patients, especially in the CCM group. To further approach the dynamics of T cell migratory events, we performed fibronectin-, TNF-α-, and CXCL12-driven migration. Peripheral blood mononuclear cells (PBMCs) and T cells from CCM patients presented an ex vivo enhanced migratory capacity driven by fibronectin alone when this ECM protein was placed in the membrane of transwell migration chambers. When TNF-α was previously placed upon fibronectin, we observed a further and significant increase in the migratory response of both PBMCs and T lymphocytes. Overall, these data suggest the existence in patients with chronic Chagas disease of a cardiac inflammatory infiltrate vector that promotes the recruitment and accumulation of activated T cells, driven in part by enhanced tissue expression of fibronectin and TNF-α, as well as the respective corresponding VLA-4 and TNF receptors.
