CD4 skin resident memory T cells preferentially colocalize with dermal Folr2 macrophages in contact hypersensitivity.

In contact hypersensitivity (CHS), local immune memory is established in previously affected skin through the formation of CD4 and CD8 tissue-resident memory T (T) cells. This memory contributes to disease recurrence by enhancing local antigen responsiveness and is maintained in the long term by T cells, particularly CD4 T cells. However, the mechanisms underlying the maintenance and reactivation of CD4 T cells remain unclear. We herein examined the cellular niches persistently interacting with CD4 T cells in naïve and CHS-healed mouse ear skin. Most CD4 T cells were scattered in the dermis and colocalized with Folr2 macrophages, a previously unrecognized skin macrophage population, suggesting a physical interaction. In contrast, fewer than 20% of CD4 T cells colocalized with dendritic cells (DCs) or other cell lineages. The administration of an anti-colony stimulating factor 1 receptor (CSF1R) antibody depleted nearly all Folr2 macrophages and several other myeloid cells, while the maintenance and reactivation of CD4 T cells as well as other αβ T cells in healed skin remained unaffected. Moreover, in macrophage-depleted healed skin, CD4 T cells did not establish new interactions with remaining antigen-presenting cells, and their contact rate with DCs remained unchanged. These results indicate that local immune memory in CHS-experienced skin is maintained and functions independently of CSF1R-dependent myeloid cells, including Folr2 macrophages, despite their predominant colocalization with skin CD4 T cells.