CD4(+) Resident Memory T Cells Mediate Long-Term Local Skin Immune Memory of Contact Hypersensitivity in BALB/c Mice

In allergic contact dermatitis (ACD) and contact hypersensitivity (CHS), the healed skin shows greater swelling than the naïve skin in the same individual upon re-exposure to the same hapten. This “local skin memory” (LSM) in healed skin was maintained for a prolonged period of time and mediated by skin CD8(+)-resident memory T (T(RM)) cells in C57BL/6 mice. However, the number of CD4(+) T cells is elevated in ACD-healed human skin, and the contribution of CD4(+) T(RM) cells to the formation of LSM currently remains unclear. We herein demonstrated that immediately after CHS subsided, the healed skin in BALB/c mice showed an accumulation of hapten-specific CD4(+) and CD8(+) T(RM) cells, with a predominance of CD4(+) T(RM) cells. The presence of CD4(+) or CD8(+) T(RM) cells in the healed skin was sufficient for the induction of a flare-up reaction upon a re-challenge. The CD4(+) and CD8(+) T(RM) cells both produced interferon-γ and tumor necrosis factor early after the re-challenge. Moreover, while CD8(+) T(RM) cells gradually decreased over time and were eventually lost from the healed skin at 40–51 weeks after the resolution of CHS, the CD4(+) T(RM) cell numbers remained elevated during this period. The present results indicate that the long-term maintenance of LSM is mediated by CD4(+) T(RM) cells, and thus CD4(+) T(RM) cells are an important target for the treatment of recurrent human ACD.