Abstract
Post Kala-azar dermal leishmaniasis (PKDL), caused by Leishmania donovani is the dermal sequel of Visceral Leishmaniasis and importantly, is the proposed disease reservoir. The survival of Leishmania parasites within monocytes/macrophages hinges on its ability to effectively nullify immune activation mechanisms. Thus, delineating the disease-promoting immune mechanisms can facilitate development of immunotherapeutic strategies. Accordingly, in the absence of an animal model, this study aimed to delineate the status of CD8+ T-cells in patients with PKDL. At disease presentation, the absence of CD4+ T-cells at lesional sites was concomitant with an overwhelming infiltration of CD8+ T-cells that demonstrated an absence of Perforin, Granzyme and Zap-70, along with an enhanced expression of Programmed Death-1 (PD-1) and the skin-homing CCL17. Additionally, the lesional CCR4+CD8+ population was associated with an enhanced expression of IL-10 and IL-5. In circulation, the enhanced CD8+CCR4+ T-cell population and raised levels of CCL17/22 was associated with an increased frequency of PD-1, while CD127 was decreased. Taken together, in PKDL, the enhanced plasma and lesional CCL17 accounted for the dermal homing of CD8+CCR4+ T-cells, that along with a concomitant upregulation of PD-1 and IL-10 mediated immune inactivation, emphasizing the need for designing immunotherapies capable of reinvigorating T-cell potency.
Highlights
Post Kala-azar dermal leishmaniasis (PKDL), caused by Leishmania donovani is the dermal sequel of Visceral Leishmaniasis and importantly, is the proposed disease reservoir
The results demonstrated an increased proportion of CD8+Chemokine Receptor 4 (CCR4)+ T-cells and CCL17/CCL22 indicative of dermal homing, while the upregulation of Programmed Death-1 (PD-1) and IL-10 suggested impaired activation of CD8+ T-cells
In patients with localised self healing Cutaneous Leishmaniasis (CL) (LCL) caused by L. major, an increased proportion of CXCR3/CD4+ and/or CD8+ T-cells provided a protective role[40], whereas, in severe forms of CL caused by L. braziliensis, increased disease severity occurred secondary to dysregulated CD8+
Summary
Post Kala-azar dermal leishmaniasis (PKDL), caused by Leishmania donovani is the dermal sequel of Visceral Leishmaniasis and importantly, is the proposed disease reservoir. In this study, the activation status of CD4+ and CD8+ T-cells, cytotoxic markers e.g. Perforin, Granzyme and p-Zap-70, inhibitory receptorProgrammed death-1 (PD-1), skin homing chemokine CCL17 and its receptor, Chemokine Receptor 4 (CCR4) along with IL-5 and IL-10 were evaluated in dermal lesions of patients with PKDL. The results demonstrated an increased proportion of CD8+CCR4+ T-cells and CCL17/CCL22 indicative of dermal homing, while the upregulation of PD-1 and IL-10 suggested impaired activation of CD8+ T-cells Taken together, this dermal homing of anergic/exhausted CD8+ T-cells supported parasite survival and disease progression in patients with PKDL
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