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Although cytolytic CD8 T cells cannot control the parasites, they significantly contribute to pathologic responses. In a murine model of cutaneous leishmaniasis, we previously found that NKG2D plays a role in the ability of cytolytic CD8 T cells to promote disease in leishmanial lesions. Here, we investigated whether NKG2D plays a role in human disease. We found that NKG2D and its ligands were expressed within lesions from\n                    <jats:italic>L<\/jats:italic>\n                    .\n                    <jats:italic>braziliensis<\/jats:italic>\n                    -infected patients and that IL-15 and IL-1\u03b2 were factors driving NKG2D and NKG2D ligand expression, respectively. Blocking NKG2D reduced degranulation by CD8 T cells in a subset of patients. Additionally, our transcriptional analysis of patients\u2019 lesions found that patients who failed the first round of treatment exhibited higher expression of\n                    <jats:italic>KLRK1<\/jats:italic>\n                    , the gene coding for NKG2D, than those who responded to treatment. These findings suggest that NKG2D may be a promising therapeutic target for ameliorating disease severity in cutaneous leishmaniasis caused by\n                    <jats:italic>L<\/jats:italic>\n                    .\n                    <jats:italic>braziliensis<\/jats:italic>\n                    infection.\n                  <\/jats:p>","DOI":"10.1371\/journal.pntd.0011552","type":"journal-article","created":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T13:31:13Z","timestamp":1692624673000},"page":"e0011552","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":15,"title":["NKG2D promotes CD8 T cell-mediated cytotoxicity and is associated with treatment failure in human cutaneous leishmaniasis"],"prefix":"10.1371","volume":"17","author":[{"given":"La\u00eds A.","family":"Sacramento","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camila","family":"Farias 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