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.