Tissue-resident memory T cells (TRM cells) have emerged as one of the immune system’s most powerful front-line defenders. Unlike circulating T cells that patrol the bloodstream, TRM cells embed within organs—such as the lung, liver, skin, and brain—where they can respond immediately to infection, cancer, or tissue injury. In many cancers, high densities of TRM cells correlate with better survival, and in chronic infections, their presence can determine whether an organ clears or tolerates a pathogen.
Yet despite their importance, the molecular cues that instruct a T cell to settle into a tissue and adopt this highly specialized identity have remained elusive. A new study led by Pandurangan Vijayanand, MD, PhD, at the La Jolla Institute for Immunology (LJI) now reveals a critical signaling axis that governs this transformation. The work, published in Science Immunology, identifies the G-protein coupled receptor GPR25 as a central determinant of TRM cell development and persistence.
“We found a new molecule that is likely to play an important role in the development and function of TRM cells,” says Vijayanand. This discovery, the first to link GPR25 to TGF-β-driven differentiation, could accelerate the development of therapeutics that selectively boost TRM cells in cancer and infectious disease—or instead, suppress them in autoimmune disorders.
A powerful yet poorly understood T-cell subset
Tissue-resident memory T cells are relatively new to immunology. Although their existence was suspected earlier, they were only formally described in 2009. Over the past decade, TRM cells have become central to research on organ-specific immunity. They are now known to participate in antiviral defense, microbial containment, anti-tumor immunity and long-term tissue protection.
“This is a super powerful cell population,” says co-first author Han Feng, PhD. TRM cells can rapidly produce cytokines, recruit other immune cells, and mount localized responses that circulating cells cannot match. Their organ specificity is what makes them so effective—but it also makes them uniquely challenging to study.
Unlike circulating memory cells, TRM cells do not recirculate through lymphoid organs. Instead, they arise when precursor cells receive tissue-specific signals that lock them into place. One molecule long implicated in this process is TGF-β, an indispensable cytokine that imprints residency across many organs. But how TGF-β shapes the transcriptional programs underlying TRM cell formation has remained unclear.
GPR25: A missing link in TRM cell differentiation
A previous transcriptomic study from the Vijayanand lab hinted at an unusual clue: TRM cells expressed extraordinarily high levels of GPR25, a receptor with no previously characterized role in T-cell biology. “That was so specific, so we knew there must be something going on with this receptor,” says Feng.
The new study confirms that GPR25 is directly induced by TGF-β and is required to sustain TGF-β’s downstream signaling pathways. In mouse models engineered to lack GPR25, TGF-β signals faded prematurely, and TRM cells failed to differentiate or persist in tissues such as the lung and liver. Without GPR25, these cells could not maintain the transcriptional program that defines TRM cells or fulfill their surveillance role.
Feng’s experiments demonstrated that GPR25-deficient mice had markedly fewer functional TRM cells following infection or tissue challenge. In contrast, modulating GPR25 activity altered the robustness of the TRM compartment, suggesting that this receptor acts as a rheostat for tissue immunity.
A druggable entry point into TRM biology
The translational implications are significant. GPR25 belongs to the GPCR superfamily, one of the most therapeutically tractable classes of receptors in biology. “These molecules are expressed on the cell membrane, so they are easy for a drug to access,” Feng explains. Nearly one-third of all FDA-approved drugs target GPCRs, underscoring their suitability for drug development.
Future therapies could theoretically activate GPR25 to boost TRM cells in tumors, chronic viral infections, or vaccine responses. In solid tumors such as lung cancer, where Vijayanand previously showed that high TRM density correlates with improved outcomes, such strategies could strengthen organ-specific immunity already known to play a decisive role in survival.
Conversely, GPR25 inhibition could help dampen TRM-driven inflammation in autoimmune diseases where tissue-resident cells contribute to pathology, such as psoriasis or inflammatory bowel disease.
“We think GPR25 is an interesting molecule full of translation potentials that worth investigating,” says Feng.
A roadmap for targeted modulation of organ-specific immunity
As interest in TRM biology accelerates, the field has been searching for actionable molecular pathways that can be manipulated without broadly altering systemic immunity. The identification of GPR25 as a receptor that both interprets and sustains TGF-β signals offers one such pathway.
More broadly, the discovery helps clarify how tissue environments shape long-term memory cell behavior. It also provides a mechanistic foundation for future work aimed at expanding, recruiting, or reprogramming TRM cells—approaches that are already being explored in cancer immunotherapy and mucosal vaccine development.
By defining a discrete, druggable signaling switch, the LJI team brings researchers closer to rationally harnessing the potent protective capacity of these organ-resident sentinels.
