Understanding Immune Cells in Tertiary Lymphoid Organ Development: It Is All Starting to Come Together

Abstract

Tertiary lymphoid organs (TLOs) are frequently observed in tissues affected by non-resolving inflammation as a result of infection, autoimmunity, cancer, and allograft rejection. These highly ordered structures resemble the cellular composition of lymphoid follicles typically associated with the spleen and lymph node compartments. Although TLOs within tissues show varying degrees of organization, they frequently display evidence of segregated T and B cell zones, follicular dendritic cell networks, a supporting stromal reticulum, and high endothelial venules. In this respect, they mimic the activities of germinal centers and contribute to the local control of adaptive immune responses. Studies in various disease settings have described how these structures contribute to either beneficial or deleterious outcomes. While the development and architectural organization of TLOs within inflamed tissues requires homeostatic chemokines, lymphoid and inflammatory cytokines, and adhesion molecules, our understanding of the cells responsible for triggering these events is still evolving. Over the past 10–15 years, novel immune cell subsets have been discovered that have more recently been implicated in the control of TLO development and function. In this review, we will discuss the contribution of these cell types and consider the potential to develop new therapeutic strategies that target TLOs.

Hyperactive gp130/STAT3‐driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development

“…Homeostatic chemokines play a central role in the development of secondary lymphoid organs and TLSs,4, 12 and our earlier data revealed transcripts for Cxcl13 , Ccl19 , Ccl21 and Cxcl12 in laser microdissected TLSs from 6‐month‐old gp130 F/F mice with well‐established gastric tumours (see Fig. 1 h ).…”

“…1 d ). TLSs also contained podoplanin (Pdpn; also called gp38) expressing cells, marking the presence of stromal cells required for lymphoid organ development, and the support of lymphocyte migration and antigen presentation4, 35 (Fig. 1 d ).…”

“…However, the mechanisms that link chronic inflammation to the development and progression of GC are ill‐defined. Tertiary lymphoid structures (TLSs; also called ectopic lymphoid structures, ELSs) are inducible lymphoid aggregates that phenotypically and functionally resemble secondary lymphoid organs 4. TLSs can develop in tissues where persistent inflammation is present, and a correlation between high TLS densities and prolonged patient survival has been reported for several cancers including breast,5, 6 lung,7, 8 melanoma,9 pancreatic10 and colorectal 11, 12.…”

“…TLS gene signatures, that include homeostatic chemokines such as CXCL13 , CCL19 and CCL21 , have the potential to represent prognostic indicators of cancer progression in melanoma13 and colorectal cancer 14, 15. Several studies propose that tumour‐associated TLSs provide a local environment for establishing and maintaining anti‐tumour immunity 4, 12. For example, clonal expansion of interferon‐(IFN)‐γ producing T cells reactive to tumour antigens, which inhibit tumour growth, have been observed in experimental mouse melanoma 16, 17.…”

Somatic mutation-associated T follicular helper cell elevation in lung adenocarcinoma

“…6 Despite the well-characterized role of infiltrating B cells and TLOs, the role of Tfh in human lung cancers remains understudied. 7 Infection models have revealed that circulating Tfh function differently from those in lymphoid tissue and correlate with opposing outcomes. 8 In human breast cancers and mouse models of colorectal cancer, increased Tfh correlates with increased survival.…”