Tertiary lymphoid structures (TLS) are organized clusters of immune cells that develop in non-lymphoid tissues, particularly in areas experiencing prolonged inflammation or disease. Unlike the body’s primary and secondary lymphoid organs, which form during development, TLS are induced later in life. These structures are gaining recognition in immunology and medicine due to their presence in various pathological conditions, including chronic infections, autoimmune diseases, and cancer.
Understanding Tertiary Lymphoid Structures
TLS often contain various immune cell types, including T cells, B cells, dendritic cells, and macrophages, resembling the cellular organization found in conventional lymph nodes. A hallmark of mature TLS is the presence of B cell zones, which can include germinal centers where B cells mature and produce antibodies, surrounded by T cell-rich areas.
These structures also feature high endothelial venules (HEVs), specialized blood vessels that facilitate the entry of immune cells from the bloodstream into the TLS. HEVs produce chemokines that attract immune cells, orchestrating their accumulation. While TLS share many similarities with secondary lymphoid organs, a key distinction is their inducible nature and formation in non-lymphoid tissues, often in response to chronic inflammation or tissue injury. Unlike encapsulated lymph nodes, TLS are not enclosed by a fibrous capsule.
How Tertiary Lymphoid Structures Form
TLS formation is triggered by chronic inflammation, which can arise from prolonged infections, autoimmune diseases, or the presence of tumors. This process, known as lymphoid neogenesis, involves a complex interplay of various cellular and molecular signals.
Key molecular players in TLS formation are chemokines and cytokines, which act as signaling molecules to attract and organize immune cells. Chemokines such as CXCL13, CCL19, and CCL21 are important, as they guide the recruitment of lymphocytes and other immune cells to the inflamed tissue. Certain immune cells, like lymphoid tissue inducer (LTi) cells, and even some cancer-associated fibroblasts, can initiate this process by expressing molecules that promote the recruitment and organization of other immune cells, leading to the structured aggregation characteristic of TLS. This dynamic and regulated process ensures that immune responses can be mounted locally where they are most needed.
Their Role in Immune Responses
Tertiary lymphoid structures function as local sites for immune responses directly within affected tissues, acting as “mini-lymph nodes” at the site of pathology. They facilitate the activation, proliferation, and differentiation of immune cells, including T and B lymphocytes, enabling a localized and sustained immune attack against persistent threats. This local immune activation can have both beneficial and detrimental consequences, depending on the specific disease context.
In some situations, such as cancer, TLS can play a beneficial role by promoting anti-tumor immunity. They can foster the activation of cytotoxic T cells and the maturation of B cells into antibody-producing plasma cells, which target tumor-associated antigens. The presence of TLS in tumors has been associated with improved patient prognosis and better responses to immunotherapies. Similarly, in chronic infections, TLS can help clear pathogens by serving as localized hubs for adaptive immune responses.
However, in autoimmune diseases, TLS can contribute to ongoing inflammation and tissue damage. In conditions like rheumatoid arthritis or lupus nephritis, these structures can perpetuate the autoimmune response by fostering the local activation of self-reactive T and B cells and the production of autoantibodies, leading to chronic tissue destruction. The specific composition and maturity of TLS can influence whether their role is protective or harmful.
Implications for Health and Medicine
Understanding tertiary lymphoid structures holds important implications for health and medicine, as they can serve as valuable indicators for disease progression and treatment response. The presence and characteristics of TLS can act as biomarkers, providing insights into the severity of certain conditions or predicting a patient’s response to therapies. For instance, in cancer, the presence of TLS is often associated with a more favorable response to immune checkpoint inhibitors, suggesting their potential as a predictive tool for immunotherapy efficacy.
Beyond their role as biomarkers, TLS are also being explored as targets for therapeutic interventions. Strategies aimed at enhancing TLS formation in tumors are being investigated to boost anti-cancer immunity. Conversely, in autoimmune diseases, research focuses on inhibiting TLS formation or function to reduce inflammation and prevent tissue damage. This paves the way for personalized medicine approaches that leverage these dynamic immune structures to improve patient outcomes.