Impaired activation of lesional CD8+ T-cells is associated with enhanced expression of Programmed Death-1 in Indian Post Kala-azar Dermal Leishmaniasis

Sci Rep. 2019 Jan 24;9(1):762. doi: 10.1038/s41598-018-37144-y.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / parasitology
  • Chemokine CCL17 / genetics
  • Female
  • Gene Expression Regulation / immunology
  • Humans
  • Interleukin-10 / genetics*
  • Interleukin-10 / immunology
  • Interleukin-7 Receptor alpha Subunit
  • Leishmania donovani / immunology*
  • Leishmania donovani / pathogenicity
  • Leishmaniasis, Visceral / genetics*
  • Leishmaniasis, Visceral / immunology
  • Leishmaniasis, Visceral / parasitology
  • Leishmaniasis, Visceral / pathology
  • Macrophages / immunology
  • Male
  • Monocytes / immunology
  • Perforin / genetics
  • Programmed Cell Death 1 Receptor / genetics*
  • Receptors, CCR4 / genetics
  • Young Adult
  • ZAP-70 Protein-Tyrosine Kinase / genetics

Substances

  • CCR4 protein, human
  • Chemokine CCL17
  • Interleukin-7 Receptor alpha Subunit
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Receptors, CCR4
  • Perforin
  • Interleukin-10
  • ZAP-70 Protein-Tyrosine Kinase