Tissue Resident Memory T Cells: Key Phenotypes and Roles

Tissue-resident memory T cells (TRM) are a subset of memory T cells that remain in peripheral tissues rather than circulating through the bloodstream. They play a crucial role in local immunity, providing rapid protection against previously encountered pathogens. Their ability to stay in tissues without recirculating distinguishes them from other memory T cell subsets and allows for immediate immune responses at infection sites.

TRM cells contribute to both protective immunity and inflammatory diseases. While they provide long-term defense, they can also drive chronic inflammation in autoimmune conditions. Researchers continue to explore their unique characteristics, including surface markers, retention mechanisms, and metabolic adaptations, to harness their potential for immunotherapies.

Key Phenotypic Markers

TRM cells are defined by distinct surface markers that differentiate them from circulating memory T cells. These markers are essential for their retention in tissues and functional properties. Among the most studied are CD69, CD103, and CD49a, each contributing to the cells’ ability to remain in specific microenvironments.

CD69

CD69 is a hallmark of TRM cells. Unlike naïve or circulating memory T cells, which downregulate CD69 upon exiting lymphoid organs, TRM cells maintain its expression, ensuring their residency. CD69 antagonizes sphingosine-1-phosphate receptor 1 (S1PR1), a molecule that facilitates lymphocyte egress, effectively anchoring TRM cells within their local environment.

Studies have demonstrated CD69 expression across multiple tissue sites, including the skin, lungs, and gastrointestinal tract. Research published in Nature Immunology (Mackay et al., 2013) showed that CD69-deficient mice exhibit reduced TRM populations in non-lymphoid tissues, reinforcing its necessity for retention. While CD69 is a key identifier of TRM cells, it is often co-expressed with other markers to fully define their phenotype.

CD103

CD103, also known as integrin αEβ7, is particularly associated with epithelial tissues. This integrin binds to E-cadherin, facilitating adhesion of TRM cells to epithelial cells. It is especially prominent in barrier tissues such as the skin, intestines, and lungs, where localized immune presence is essential.

A study in The Journal of Experimental Medicine (Sheridan et al., 2014) demonstrated that CD103-deficient mice exhibit impaired TRM localization in mucosal tissues, leading to altered immune surveillance. While not universally expressed across all TRM subsets, CD103 is strongly associated with epithelial-associated TRM populations. Its expression is often induced by local transforming growth factor-beta (TGF-β) signaling, reinforcing its role in tissue adaptation.

CD49a

CD49a (integrin α1) defines a subset of TRM cells, particularly in deeper tissues such as the dermis and skeletal muscle. Unlike CD103, which associates primarily with epithelial cells, CD49a binds to collagen, allowing TRM cells to persist in extracellular matrix-rich environments.

A study in Nature Communications (Cheuk et al., 2017) identified CD49a as a distinguishing feature of skin TRM cells with cytotoxic potential. CD49a-positive TRM cells mediate tissue surveillance by interacting with collagen IV, a structural component of the basement membrane. CD49a expression is also linked to functional specialization, with CD49a-expressing TRM cells exhibiting distinct effector properties compared to their CD49a-negative counterparts.

Together, CD69, CD103, and CD49a define TRM cells and their tissue-specific adaptations. Each marker contributes uniquely to retention and localization, shaping tissue-resident immune populations.

Tissue Specific Localization

TRM cells establish themselves in diverse anatomical sites, adapting to the unique microenvironments of each tissue. Their distribution is dictated by structural, molecular, and environmental cues that shape their residency patterns. The skin, lungs, gastrointestinal tract, and brain each provide a distinct niche where TRM cells integrate into the local architecture.

In barrier tissues such as the skin and mucosal surfaces, TRM cells are positioned strategically for surveillance. The epidermis harbors CD103⁺ TRM cells that adhere tightly to keratinocytes via E-cadherin interactions, forming a dense network for rapid responses. The dermis is enriched with CD49a⁺ TRM cells, which persist through interactions with collagen. Intravital microscopy studies reveal that skin TRM cells exhibit minimal migration, reinforcing their long-term anchorage.

Lung TRM cells persist in a dynamic environment characterized by constant airflow and cellular turnover. These cells are often located near alveolar epithelial cells, where they interact with structural components such as fibronectin and laminin. Unlike skin TRM cells, lung-resident populations show a degree of motility, patrolling alveolar spaces while remaining confined to the tissue. Research published in Science Immunology (Beura et al., 2018) demonstrated that lung TRM cells are maintained through periodic exposure to local cytokines rather than proliferation.

In the gastrointestinal tract, TRM cells navigate commensal microbiota and dietary antigens. Intestinal TRM cells primarily localize within the lamina propria and intraepithelial compartments, interacting closely with epithelial cells and stromal components. TGF-β plays a significant role in maintaining CD103 expression, reinforcing epithelial attachment. Unlike lung TRM cells, intestinal TRM populations exhibit a more sessile phenotype, remaining in their initial sites of residence.

Beyond peripheral tissues, TRM cells also localize in immune-privileged sites such as the brain, where they adopt a distinct transcriptional profile suited for long-term survival. Brain-resident TRM cells avoid excessive activation to prevent neuroinflammation yet remain poised for rapid responses. The blood-brain barrier limits immune cell trafficking, making TRM cells a primary source of adaptive immunity within the central nervous system.

Mechanisms Of Tissue Retention

TRM cells remain embedded in tissues through adhesion molecules, chemokine signaling, and transcriptional regulation. Unlike circulating memory T cells, which recirculate through the bloodstream and lymphatic system, TRM cells establish long-term residency by modifying their migratory capacity.

Adhesion molecules like CD103 and CD49a play a significant role in anchoring TRM cells by binding to tissue-specific ligands such as E-cadherin and collagen. These interactions provide mechanical stability and promote survival signals that prevent apoptosis. Additionally, downregulation of S1PR1 prevents TRM cells from responding to egress signals that would direct them back into circulation.

Local chemokine gradients reinforce retention by directing TRM cells to tissue niches. Chemokines such as CXCL9, CXCL10, and CCL5 create an environment that favors TRM accumulation. Corresponding chemokine receptors, including CXCR3 and CCR5, enable TRM cells to migrate within tissues while remaining confined to their microenvironment.

Transcription factors Runx3 and Hobit drive TRM identity by promoting genes necessary for tissue residency while suppressing those associated with recirculation. Runx3 enhances adhesion molecule and chemokine receptor expression while inhibiting pathways that promote lymphatic exit. Genetic knockout studies show that the absence of these transcription factors prevents TRM cells from establishing long-term residency.

Relationship To Circulating Memory T Cells

TRM and circulating memory T cells represent distinct yet complementary branches of the adaptive immune system. While both originate from activated T cells, their developmental trajectories diverge based on environmental cues. Circulating memory T cells, including central memory (TCM) and effector memory (TEM) subsets, patrol the body via the bloodstream and lymphatic system, while TRM cells establish long-term residency in specific tissues.

Local tissue signals during immune resolution determine whether a memory T cell adopts a circulating or resident phenotype. TGF-β promotes TRM differentiation while suppressing molecules required for lymphatic egress, such as S1PR1. In contrast, circulating memory T cells maintain molecules that facilitate trafficking between blood and lymphoid tissues, such as CCR7 and CD62L.

Cytokine Secretion Patterns

TRM cells contribute to immune defense through cytokine production, shaping the local tissue environment. Their rapid secretion of pro-inflammatory and regulatory cytokines upon antigen recognition orchestrates protective responses.

Interferon-gamma (IFN-γ) enhances local antimicrobial defense by activating macrophages, increasing adhesion molecule expression, and recruiting immune cells. Tumor necrosis factor-alpha (TNF-α) further activates nearby immune cells and reinforces inflammation. While beneficial for pathogen clearance, excessive cytokine production can drive chronic inflammation.

In mucosal tissues, TRM cells produce interleukin-17 (IL-17) and interleukin-22 (IL-22). IL-17 recruits neutrophils, while IL-22 promotes epithelial barrier integrity and tissue repair. The balance between pro-inflammatory and tissue-protective cytokines ensures effective immunity without excessive tissue damage.

Metabolic Features

TRM cells adapt their metabolism to persist in non-lymphoid tissues, where nutrient availability and oxygen levels vary. Unlike circulating memory T cells, which rely primarily on glycolysis, TRM cells favor fatty acid oxidation (FAO) to sustain energy production.

FAO supports TRM longevity and functional stability, regulated by PGC-1α, which enhances mitochondrial biogenesis. TRM cells also exhibit increased mitochondrial respiration and upregulate autophagy-related pathways, allowing them to recycle intracellular components for energy production. These metabolic adaptations enable TRM cells to maintain residency without continuous replenishment from circulation.