Tertiary Lymphoid Structure: Role in Inflammation and Cancer

Lymphoid structures typically form in specialized organs like lymph nodes, but under certain conditions, they develop in non-lymphoid tissues. These formations, known as tertiary lymphoid structures (TLS), emerge during chronic inflammation and some cancers, influencing immune responses in both beneficial and detrimental ways.

Understanding TLS is crucial as they can enhance immune defense or contribute to disease progression depending on the context.

Structural Components

Tertiary lymphoid structures (TLS) exhibit a complex organization resembling secondary lymphoid organs but arise in non-lymphoid tissues in response to persistent inflammation. Their architecture includes B-cell follicles, T-cell zones, and specialized stromal networks supporting their formation and maintenance. Unlike lymph nodes, which develop during embryogenesis, TLS emerge dynamically in adult tissues, adapting to local conditions. They form in diverse locations, from inflamed synovial tissue in rheumatoid arthritis to tumors in various cancers.

A defining feature of TLS is the B-cell follicle, often containing germinal center-like structures where B cells proliferate, undergo somatic hypermutation, and mature. Follicular dendritic cells (FDCs) support these follicles by presenting antigens and selecting high-affinity B-cell clones. The presence of FDC networks within TLS suggests functional parallels to lymphoid organs, sustaining long-term antigen presentation and immune interactions. Additionally, high endothelial venules (HEVs) are frequently observed within TLS, recruiting circulating lymphocytes through adhesion molecules such as PNAd and CCL21, ensuring a continuous immune cell supply.

Surrounding the B-cell follicle, the T-cell zone consists of CD4+ and CD8+ T cells interspersed with antigen-presenting cells like dendritic cells and macrophages. This area is organized around fibroblastic reticular cells (FRCs), which provide structural support and facilitate T-cell activation and migration. FRCs produce chemokines such as CCL19 and CCL21, guiding T cells and dendritic cells into the TLS. These stromal elements distinguish mature TLS from transient immune cell aggregates, creating a scaffold for sustained immune interactions.

Signals That Drive Formation

TLS formation is driven by molecular signals responding to persistent inflammatory cues in non-lymphoid tissues. Unlike primary and secondary lymphoid organogenesis, which follows a preprogrammed sequence, TLS develop dynamically in response to chronic immune activation. This adaptability allows TLS to emerge in autoimmune diseases and tumor microenvironments, where sustained antigenic stimulation and tissue stress foster their assembly.

Lymphotoxin (LT) signaling is central to initiating TLS, particularly through the LTα1β2 heterotrimer, which engages the LTβ receptor (LTβR) on stromal cells. This activates the NF-κB pathway, upregulating adhesion molecules and chemokines that recruit immune cells. Studies in murine models show that blocking LTβR prevents TLS formation, highlighting its necessity in early organization. Additionally, tumor necrosis factor-alpha (TNF-α) and interleukin-17 (IL-17) contribute to stromal cell activation, reinforcing the inflammatory environment required for TLS persistence. These cytokines sustain lymphoid chemokine production and influence fibroblastic reticular cell differentiation, supporting TLS structure.

Chemokines such as CXCL13, CCL19, and CCL21 are essential for immune cell recruitment and compartmentalization. CXCL13, produced by stromal and follicular dendritic cells, attracts B cells via the CXCR5 receptor, facilitating B-cell follicle formation. Meanwhile, CCL19 and CCL21, secreted by fibroblastic reticular cells, guide T cells and dendritic cells through interactions with CCR7. The coordinated expression of these chemokines establishes distinct functional zones within TLS, mirroring secondary lymphoid organs. Experimental models show that ectopic CXCL13 expression can induce lymphoid-like aggregates, but sustained TLS maturation requires multiple chemokines and cytokines to maintain immune cell influx and retention.

Immune Cell Localization

The spatial distribution of immune cells within TLS follows an organized pattern resembling conventional lymphoid organs. Chemokine gradients, adhesion molecules, and cellular interactions dictate immune cell recruitment and retention. B cells, T cells, dendritic cells, and stromal components each occupy defined regions, facilitating antigen presentation and immune communication. The arrangement of these cells varies based on the local tissue context, whether in chronic inflammation or tumor microenvironments.

B cells are concentrated in follicles, often forming germinal center-like structures where they proliferate and differentiate. CXCL13 expression attracts CXCR5-expressing B cells to these regions. Follicular dendritic cells (FDCs) provide a scaffold for antigen retention and presentation, supporting B-cell maturation. The density and organization of these follicles vary with TLS development, with mature TLS displaying secondary lymphoid organ-like features, including dark and light zones for affinity maturation. Immature TLS, in contrast, show loosely arranged B-cell clusters without clear follicular structures.

Adjacent to the B-cell compartment, T cells aggregate in zones enriched with CCL19 and CCL21, produced by fibroblastic reticular cells (FRCs). These chemokines attract CCR7-expressing naïve and central memory T cells, guiding their migration and retention within the TLS. The T-cell zone often surrounds the B-cell follicle, resembling lymph nodes where T cells interact with antigen-presenting dendritic cells (DCs). Within this region, CD4+ helper T cells and CD8+ cytotoxic T cells engage in antigen recognition and activation, driving adaptive immune responses. The density of T cells within TLS varies based on the inflammatory context, with some TLS exhibiting a predominance of T cells over B cells, particularly in diseases where cellular immunity dominates.

Association With Chronic Inflammation

TLS frequently emerge in tissues experiencing prolonged inflammation, where persistent immune activation reshapes local architecture. Their presence has been documented in autoimmune diseases, chronic infections, and fibrotic disorders, linking sustained inflammation to TLS development. Unlike transient immune infiltrates that dissipate after infection, TLS persist due to ongoing antigenic stimulation, creating a self-sustaining cycle of local immune activity. This prolonged presence can exacerbate pathology by driving chronic tissue damage and fibrosis.

Autoimmune conditions such as rheumatoid arthritis (RA) and Sjögren’s syndrome illustrate this relationship, as TLS are frequently detected in synovial tissues and salivary glands, respectively. In RA, synovial TLS contribute to ectopic germinal center formation, where autoreactive B cells undergo affinity maturation, potentially enhancing autoantibody production. Similarly, in Sjögren’s syndrome, TLS in salivary glands correlate with disease severity, serving as reservoirs for autoreactive lymphocytes. The localized immune activity within these structures sustains inflammation and reinforces disease progression.

Role In Cancer Settings

TLS play a complex role in the tumor microenvironment, influencing immune responses in both protective and detrimental ways. Their presence in solid tumors has been linked to improved patient outcomes in cancers such as non-small cell lung cancer, colorectal cancer, and melanoma. In these cases, TLS serve as local hubs for immune activation, fostering interactions between antigen-presenting cells and lymphocytes that enhance adaptive immune responses. The density and maturity of TLS within tumors often determine their impact, with well-organized structures, including germinal centers and high endothelial venules (HEVs), associated with better prognosis. TLS may act as in situ sites of immune education, priming T and B cells for effective tumor recognition and elimination.

However, TLS do not always promote anti-tumor immunity. In some malignancies, such as pancreatic and hepatocellular cancers, TLS can create an immunosuppressive niche. Regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) within TLS can dampen cytotoxic responses, allowing tumor growth. Additionally, B cells within TLS have been implicated in tumor-promoting inflammation through the production of immunosuppressive cytokines like IL-10. These opposing roles highlight the complexity of TLS in cancer and underscore the importance of understanding their functional state within specific tumor types.