CD69 is indispensable for the development of functional local immune memory in murine contact hypersensitivity

Local immune memory develops at the site of antigen exposure and facilitates a rapid and strong local adaptive defense upon re-exposure. Resident memory T cells (TRM) play a role in local immune memory, and their cell-surface molecules CD69 and CD103 promote their tissue residency. However, the contribution of these molecules to skin immune memory remains unclear. Here, by inducing CHS in CD69-deficient (CD69KO) and CD103-deficient mice, where different degrees of TRM contribution are observed by repeated challenges on the right ear and a single challenge on the left ear, we found that the deficiency of CD69 but not CD103, leads to impaired CHS upon repeated antigen challenges, even although TRM-like CD8 T cells developed at the challenged site of CD69KO. CHS responses in both ears were diminished in CD69KO by FTY720 or CD8 neutralization, suggesting that CHS in CD69KO is ascribed to circulating CD8 T cells and that the developed TRM-like CD8 T cells do not behave as TRM. The infiltration of macrophages was reduced in the re-challenged site of CD69KO, along with the downregulation of Cxcl1 and Cxcl2. Thus, CD69 is considered essential for an effective recall response, involving the development of functional TRM and the recruitment of macrophages.