How PD-1 Guides T Cells to Build Lasting Immunity in Skin

Weill Cornell Medicine researchers have identified an important function for PD-1, a molecule traditionally known for suppressing immune cells, in helping T cells develop into long-lived defenders in the skin called resident memory T cells (T_RM). These T_RM cells remain fixed in the skin and provide a rapid immune response against repeated infections or cancer. The study, published in Nature Immunology, shows that early in infection, PD-1 acts like a guiding mechanism, steering T cells to become protective T_RM and establish themselves at the right location. 

This insight is significant because PD-1 is the target of immune checkpoint inhibitor drugs used for cancer therapy, especially melanoma. While these drugs work by blocking PD-1 to unleash the immune system against tumors, nearly 40% of patients experience skin-related side effects such as rashes and itching, as well as issues in other epithelial tissues. The researchers found that PD-1 is critical for forming and anchoring memory T cells in skin, indicating that disruption of PD-1 function could contribute to these adverse effects.

The team, led by Niroshana Anandasabapathy, demonstrated in mice that blocking PD-1 early after infection—either through antibodies or genetically modified T cells lacking PD-1—resulted in poor development of memory T cells and failure to retain them in skin. “We showed genetically, pharmacologically and with imaging that you need PD-1 to form resident memory T cells,” Dr. Anandasabapathy said.

The study also highlighted the role of TGF-β, a signaling molecule involved in immune cell regulation. The researchers found that when PD-1 activity was blocked, adding TGF-β could restore the ability of T cells to become T_RM cells, indicating PD-1 helps T cells engage TGF-β signaling to develop memory specifically in the skin. “PD-1 strongly selects the resident memory T cells that stay in the skin by helping them use TGF-β,” Dr. Anandasabapathy explained.

These findings suggest that timing and context are crucial in therapies targeting PD-1. Early blockade of PD-1 might prevent the formation of protective T_RM cells and lead to side effects observed in patients treated with immune checkpoint inhibitors. Understanding this mechanism could inform improved cancer treatments that minimize adverse immune reactions and could impact approaches for autoimmune conditions where PD-1 modulation is considered.