T helper 1 effector memory CD4⁺ T cells protect the skin from poxvirus infection

Poxvirus infections of the skin are a recent emerging public health concern, yet the mechanisms that mediate protective immunity against these viral infections remain largely unknown. Here, we show that T helper 1 (Th1) memory CD4⁺ T cells are necessary and sufficient to provide complete and broad protection against poxvirus skin infections, whereas memory CD8⁺ T cells are dispensable. Core 2 O-glycan-synthesizing Th1 effector memory CD4⁺ T cells rapidly infiltrate the poxvirus-infected skin microenvironment and produce interferon γ (IFNγ) in an antigen-dependent manner, causing global changes in gene expression to promote anti-viral immunity. Keratinocytes express IFN-stimulated genes, upregulate both major histocompatibility complex (MHC) class I and MHC class II antigen presentation in an IFNγ-dependent manner, and require IFNγ receptor (IFNγR) signaling and MHC class II expression for memory CD4⁺ T cells to protect the skin from poxvirus infection. Thus, Th1 effector memory CD4⁺ T cells exhibit potent anti-viral activity within the skin, and keratinocytes are the key targets of IFNγ necessary for preventing poxvirus infection of the epidermis.