In the presence of Trypanosoma cruzi antigens, activated peripheral T lymphocytes retained in the liver induce a proinflammatory phenotypic and functional shift in intrahepatic T lymphocyte

Abstract

In secondary lymphoid organs, pathogen‐derived and endogenous danger molecules are recognized by pattern recognition receptors, leading to adaptive proinflammatory immune responses. This conceptual rule does not apply directly to the liver, as hepatic immune cells tolerate gut‐derived bacterial molecules from the flora. Therefore, the recognition of danger and proinflammatory stimuli differs between the periphery and the liver. However, the tolerant nature of the liver must be overcome in the case of infections or cancer, for example. The central paradigm is the basis for danger recognition and the balance between inflammation and tolerance in the liver. Here, we observed functional integration, with activated peripheral T lymphocytes playing a role in the induction of a proinflammatory environment in the liver in the presence of Trypanosoma cruzi antigens. When only parasite extract was orally administered, it led to the up‐regulation of hepatic tolerance markers, but oral treatment plus adoptively transferred activated splenic T lymphocytes led to a proinflammatory response. Moreover, treated/recipient mice showed increased levels of TNF, IFN‐γ, IL‐6, and CCL2 in the liver and increased numbers of effector and/or effector memory T lymphocytes and F4/80+ cells. There was a reduction in FoxP3+ Treg cells, NKT cells, and γδ T lymphocytes with increased liver damage in the presence of activated peripheral T cells. Our results show that the induction of a proinflammatory liver response against T. cruzi danger molecules is at least partially dependent on cooperation with activated peripheral T cells.

New Biomarker in Chagas Disease: Extracellular Vesicles Isolated from Peripheral Blood in Chronic Chagas Disease Patients Modulate the Human Immune Response

“…After incubation with circulating EVs from patients, macrophages produced more IFN- γ than healthy controls. Another point to take into consideration is that almost all of the patients were older than the controls, so a combination of both age and infection might be responsible for the increase in IFN- γ levels and the establishment of a basal proinflammatory environment, which in turn could be related to cardiac tissue damage characteristic of chronic symptomatic Chagas disease [ 48 , 49 ].…”

After Experimental Trypanosoma cruzi Infection, Dying Hepatic CD3+TCRαβ+B220+ T Lymphocytes Are Rescued from Death by Peripheral T Cells and Become Activated

“…Taken together, our results indicated that at least part of the liver CD3 + B220 + CD117 + T lymphocyte population could be rescued from death after infection, downregulating the expression of B220, remaining CD117 + , and assuming a phenotype of viable activated T cells. We published recently that, in the acute phase of experimental T. cruzi infection, activated peripheral T lymphocytes induce the activation of stromal hepatic T lymphocyte and lead to a local proinflammatory immune response [ 21 ]. Thus, we studied whether activated peripheral T lymphocytes could rescue hepatic CD3 + B220 + CD117 + T lymphocytes from death and induce cellular activation.…”

“…lymphocytes induce the activation of stromal hepatic T lymphocyte and lead to a local proinflammatory immune response [21]. Thus, we studied whether activated peripheral T lymphocytes could rescue hepatic CD3 + B220 + CD117 + T lymphocytes from death and induce cellular activation.…”

The Liver and the Hepatic Immune Response in Trypanosoma cruzi Infection, a Historical and Updated View

“…Moreover, one of the significant roles of NK cells and CD4 + T lymphocytes in liver protection and infection control is interferon-gamma production (IFN-γ) [ 45 ]. In addition, we observed that experimental murine infection leads to increased hepatic regulatory T (Treg) cell numbers, higher expression of programmed death ligand 1 (PD-L1 or B7-H1) in the liver stroma, increased blood activity of ALT and AST transaminases, and other alterations [ 46 ].…”

“…KCs express MHC-I and MHC-II and co-stimulatory molecules such as B7.1, B7.2 [ 71 ], and CD40, although at lower levels than hepatic dendritic cells (HDC). Under normal conditions, KCs secrete prostaglandin E2 (PGE2), transforming growth factor beta (TGF-β), and IL-10 [ 46 ], and express Fas-L and PD-L1 on the cell membrane [ 72 , 73 ] ( Figure 2 ), playing a role in maintaining immune hyporesponsiveness/immunotolerance and leading to the differentiation of more hepatic Treg cells.…”