Dengue infection elicits skin tissue-resident and circulating CD8 ⁺ T cells associated with protection from hospitalization

Dengue is spreading globally, and there is urgent need to define immune correlates of protection for this disease. Dengue infection first occurs in the skin following the bite of an infected mosquito; however, knowledge of host immune responses within this site remains sparse. We investigated the phenotypic, functional, and transcriptional profiles of skin and blood T cells in 73 patients with dengue and 10 healthy volunteers. We show that the skin T cell compartment undergoes marked reshaping and is strongly enriched with proliferating CD4⁺ and CD8⁺ T cells compared with the blood of patients. Activated skin CD8⁺ T cells expressed a core transcriptional signature of tissue-resident memory T (T_RM) cells, supporting their differentiation to the T_RM cell lineage during infection. The magnitude of skin and blood CD8⁺ T cell responses were associated with protection from hospitalization in this cohort. These data support a protective role of skin-resident and circulating CD8⁺ T cells in dengue and warrant evaluation of vaccination strategies inducing skin T_RM cells to enhance protective immunity.