Compartmentalized cytotoxic immune response leads to distinct pathogenic roles of natural killer and senescent CD8 ⁺ T cells in human cutaneous leishmaniasis.

Publisher: Blackwell Scientific Publications Country of Publication: England NLM ID: 0374672 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1365-2567 (Electronic) Linking ISSN: 00192805 NLM ISO Abbreviation: Immunology Subsets: MEDLINE

Original Publication: Oxford : Blackwell Scientific Publications

Cytotoxicity, Immunologic*; Killer Cells, Natural/*pathology ; Leishmania braziliensis/*pathogenicity ; Leishmaniasis, Cutaneous/*pathology ; Skin/*pathology ; T-Lymphocytes, Cytotoxic/*pathology; CD56 Antigen/genetics ; CD56 Antigen/immunology ; CD57 Antigens/genetics ; CD57 Antigens/immunology ; Case-Control Studies ; Cellular Senescence/immunology ; Female ; Gene Expression Regulation ; Host-Parasite Interactions/genetics ; Host-Parasite Interactions/immunology ; Humans ; Interferon-gamma/genetics ; Interferon-gamma/immunology ; Killer Cells, Natural/immunology ; Killer Cells, Natural/parasitology ; Lectins, C-Type/genetics ; Lectins, C-Type/immunology ; Leishmania braziliensis/immunology ; Leishmaniasis, Cutaneous/immunology ; Leishmaniasis, Cutaneous/parasitology ; Male ; Oligosaccharides/genetics ; Oligosaccharides/immunology ; Receptors, Immunologic/genetics ; Receptors, Immunologic/immunology ; Severity of Illness Index ; Sialyl Lewis X Antigen/analogs & derivatives ; Sialyl Lewis X Antigen/genetics ; Sialyl Lewis X Antigen/immunology ; Signal Transduction ; Skin/immunology ; Skin/parasitology ; T-Lymphocytes, Cytotoxic/immunology ; T-Lymphocytes, Cytotoxic/parasitology

Cytotoxic activity mediated by CD8 ⁺ T cells is the main signature of the immunopathogenesis of cutaneous leishmaniasis (CL). Here, we performed a broad evaluation of natural killer (NK) cell phenotypic and functional features during cutaneous leishmaniasis. We demonstrate for the first time that CL patients present the accumulation of circulating NK cells with multiple features of replicative senescence including low proliferative capacity and shorter telomeres, elevated expression of CD57, KLRG1 but diminished CD27 stimulatory receptor expression. Moreover, they exhibited higher cytotoxic and inflammatory potential than age-matched controls. The accumulation of circulating senescent NK cells (CD56 ^dim  CD57 ^bright ) correlated positively with skin lesion size in the same patients, suggesting that they, like circulating senescent CD8 ⁺ T cells, may contribute to the immunopathology of CL. However, this senescent population had lower cutaneous lymphocyte antigen expression and so had diminished skin-homing potential compared with total or senescent CD8 ⁺ T cells. This was confirmed in CL skin lesions where we found a predominance of CD8 ⁺ T cells (both senescent and non-senescent) that correlated with the severity of the disease. Although there was also a correlation between the proportions of senescent NK cells (CD56 ⁺  CD57 ⁺ ) in the skin and lesion size, this was less evident. Collectively our results demonstrate first-hand that senescent cytotoxic cells may mediate skin pathology during human cutaneous leishmaniasis. However, as senescent cytotoxic CD8 ⁺ T cells predominate in the skin lesions, they may have a greater role than NK cells in mediating the non-specific skin damage in CL.
(© 2020 John Wiley & Sons Ltd.)

Comment in: Immunol Cell Biol. 2020 Jul;98(6):431-433. (PMID: 32406096)

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MR/N017749/1 United Kingdom MRC_ Medical Research Council; MR/P00184X/1 United Kingdom MRC_ Medical Research Council; 72939273/16 United Kingdom MRC_ Medical Research Council; MR/T015853/1 United Kingdom MRC_ Medical Research Council; MR/M003833/1 United Kingdom MRC_ Medical Research Council

Keywords: Leishmania braziliensis; CD8+ T cells; cellular senescence; cutaneous leishmaniasis; immunopathology; natural killer cells

0 (6-sulfo sialyl Lewis X)
0 (CD56 Antigen)
0 (CD57 Antigens)
0 (KLRG1 protein, human)
0 (Lectins, C-Type)
0 (NCAM1 protein, human)
0 (Oligosaccharides)
0 (Receptors, Immunologic)
0 (Sialyl Lewis X Antigen)
82115-62-6 (Interferon-gamma)

Date Created: 20200112 Date Completed: 20200727 Latest Revision: 20210402

20231215

PMC7078002

10.1111/imm.13173

31925782