Immunofluorescence microscopy image of a mouse epidermis showing high-density resident memory T cells (green) 60 days after vaccinia-virus infection. Image credit: Weiss et al. (CC BY 4.0)
We are constantly exposed to a wide array of pathogens in our environment. This would be detrimental to our survival if it were not for the immune system’s ability to adapt. Each time the body encounters pathogens, it develops an immunological memory that allows it to mount a quick defense response. Recent research has shown that immunological memory is not confined to immune organs like lymph nodes and spleen. Instead, a large proportion is maintained in peripheral tissues at sites of prior infection.
These local cells, known as tissue-resident memory T cells (TRM), provide the first line of defense against repeated infections. TRM develop from circulating precursors of memory T cells after pathogen exposure and then permanently reside in these tissues. The ability to mount pathogen-specific responses is a hallmark of immunological memory. Therefore, knowing how prior antigen exposure shapes TRM development is critical for understanding peripheral immunity. However, the signals that drive T cells to become TRM remain incompletely understood.
Using an acute viral infection model in mice, Weiss et al. investigated how local infection affects the differentiation and function of TRM in the skin. TRM cells were generated through skin infection with a poxvirus strain, and immune responses were measured using immunofluorescence, flow cytometry, and approaches that distinguish circulating from resident T cells.
The results showed that T cells must encounter pathogen-derived antigens directly in the skin, in addition to in the lymph nodes, for the effective development of TRM, which are capable of mounting stronger recall responses. Their long-term survival in the skin depended on signaling through the transforming growth factor-β (TGFβ) pathway, which is activated by skin cells and enhanced in T cells that encountered pathogens within the epidermis.
TRM play important roles in cancer surveillance, pathogen clearance and vaccine response, but they can also contribute to disease when dysregulated, as seen in conditions such as psoriasis, vitiligo and graft-versus-host disease. Understanding the factors that promote TRM fitness may enable strategies for making these cells more effective in fighting infections. Further, TGFß represents a possible therapeutic target to selectively modulate TRM activity when these cells become harmful.
