T-cell tolerance and exhaustion in the clearance of Echinococcus multilocularis: role of inoculum size in a quantitative hepatic experimental model

Abstract

The local immune mechanisms responsible for either self-healing or sustained chronic infection are not clear, in the development of E. multilocularis larvae. Here, we developed a suitable experimental model that mimics naturally infected livers, according to the parasite load. We demonstrated that local cellular immunity and fibrogenesis are actually protective and fully able to limit metacestode growth in the liver of low or medium dose-infected mice (LDG or MDG), or even to clear it, while impairment of cellular immunity is followed by a more rapid and severe course of the disease in high dose-infected mice (HDG). And recruitment and/ or proliferation of memory T cells (including CD4 Tem, CD8 Tcm and CD8 Tem) and imbalance of T1/T2/T17/Treg-type T cells in liver were not only associated with clearance of the parasite infection in LDG, but also with increased hepatic injury in HDG; in particular the dual role of CD8 T cells depending on the parasite load and the various stages of metacestode growth. Besides, we first demonstrate the association between LAG3- or 2B4-expressing T cells exhaustion and HD inocula in late stages. Our quantitative experimental model appears fully appropriate to study immunomodulation as a therapeutic strategy for patients with Alveolar Echinococcosis.

Immune Exhaustion of T Cells in Alveolar Echinococcosis Patients and Its Reversal by Blocking Checkpoint Receptor TIGIT in a Murine Model

“…TIGIT + Treg cells appear uniquely capable of suppressing T h 1-type responses, as opposed to T h 2 responses. (31) T-cell exhaustion actually plays a role in E. multilocularis metacestode growth (6,8) in addition to the well-described immune tolerance mediated by Treg cells and regulatory cytokines in intermediate hosts with chronic infection. (1,2) Although the precise mechanisms remain to be elucidated by further experiments, our findings showed that the treatment with anti-TIGIT mAb reduced the liver metacestode load, together with a significantly increased T h 1-type T-cell response in liver and spleen, including elevated IL-2, IFN-γ, and TNF-α production.…”

“…Many studies have shown that cellular immunity affects the development of AE lesions, and that AE is more severe, with a faster course, when there is some degree of impairment of the functional activity of T cells . Persistence of E. multilocularis is associated with a chronic granulomatous inflammation, leading to the disruption of the normal function of T cells, which is nowadays referred to as “functional exhaustion.” Recent reports have also shown that E. multilocularis infection is associated with the expression of “checkpoint” receptors that are known to limit the activity of parasite‐specific lymphocytes. We and others have shown that the receptors programmed cell‐death 1 (PDCD1), 2B4 (SLAMf4, CD244), and lymphocyte‐activation gene 3 (LAG3) are aberrantly expressed during chronic infection, and that they contribute to “exhausted” parasite‐induced T‐cell response and lead to the maintenance of E. multilocularis survival .…”

“…Persistence of E. multilocularis is associated with a chronic granulomatous inflammation, leading to the disruption of the normal function of T cells, which is nowadays referred to as “functional exhaustion.” Recent reports have also shown that E. multilocularis infection is associated with the expression of “checkpoint” receptors that are known to limit the activity of parasite‐specific lymphocytes. We and others have shown that the receptors programmed cell‐death 1 (PDCD1), 2B4 (SLAMf4, CD244), and lymphocyte‐activation gene 3 (LAG3) are aberrantly expressed during chronic infection, and that they contribute to “exhausted” parasite‐induced T‐cell response and lead to the maintenance of E. multilocularis survival . Observations in humans and experimental studies in animals suggest that, in the absence of fully effective antiparasitic chemotherapy for AE, modulation of the host immune response, specifically, blocking the coinhibitory receptors (e.g., PDCD1), could be envisaged to fight against the parasite and to prevent the disease and/or its complications.…”

Immunotherapy of alveolar echinococcosis via PD‐1/PD‐L1 immune checkpoint blockade in mice

“…A recent study showed that upregulation of PD‐1 on CD4 + CD25 + T cells is associated with immunosuppression in liver of mice infected with E. multiloculari s . Echinococcus multilocularis proliferation and some malignant tumours are both sharing similar features such as local immune evasion, induction of tolerance and disruption of T cell signalling, and T cell exhaustion at late stage of infection . Monoclonal antibodies targeting PD‐1 or PD‐L1 are in clinical use demonstrating high efficacy in lung, colon, head, neck and gastric cancers, in addition to renal cell carcinoma and melanoma …”

Ethylenecarbodiimide-fixed splenocytes carrying whole islet antigens decrease the incidence of diabetes in NOD mice <i>via</i> down-regulation of effector memory T cells and autoantibodies

“…Imbalance of Th1&Th17 and Tregs is crucial for generation of increasing T EMs in T1DM [37]. While some studies have shown that tolerance-inducing therapies can lead to an increase in Tregs in lymphoid and nonlymphoid target tissue, conversely, it is difficult to inhibit T EMs formation in autoimmunity diseases [38].…”