Potential of Cells and Cytokines/Chemokines to Regulate Tertiary Lymphoid Structures in Human Diseases

Abstract

Tertiary lymphoid structures (TLS) are ectopic lymphoid tissues involved in chronic inflammation, autoimmune diseases, transplant rejection and cancer. They exhibit almost all the characteristics of secondary lymphoid organs (SLO), which are associated with adaptive immune responses; as such, they contain organized B-cell follicles with germinal centers, distinct areas containing T cells and dendritic cells, high endothelial venules, and lymphatics. In this review, we briefly describe the formation of SLO, and describe the cellular subsets and molecular cues involved in the formation and maintenance of TLS. Finally, we discuss the associations of TLS with human diseases, especially autoimmune diseases, and the potential for therapeutic targeting.

Keywords: Autoimmunity; Inflammation; Tertiary lymphoid structures.

Figure 1. Potential of cells and cytokines/chemokines to regulate the induction and maintenance of Tertiary Lymphoid Structures (TLS). ① Cells of various types, especially CD3⁻CD4⁺CD25⁺ LTi cells and stromal cells, initiate TLS formation. B cells, T cells, and M1-polarized proinflammatory macrophages can substitute for LTi cells. LTi cells accumulate in the presence of CXCL13 and interleukin-7 (IL-7) and their receptors such as CXCR5 and IL-7R. LTi cells interact with antigen-specific CD4⁺ memory T cells via OX40 and CD30. ② Leukocytes from the circulation are recruited to inflammatory sites in response to certain chemokines and regulated by cytokines. Stromal cells secret several chemokines, including CXC-chemokine ligand 13 (CXCL13), CC-chemokine ligand 21 (CCL21) and CCL19, which are responsible for the recruitment of B and T cells, respectively. IL-23 can efficiently induce IL-22, which regulates the production of CXCL13, thereby orchestrating B-cell clustering, lymphoid aggregation, and autoantibody production in the TLS. ③ Various cell types and cytokines are involved in maintaining TLS formation: a) B cells, which accumulate in the follicular DC network, are the major TLSs component. Most TLS exhibit B cell class switching, affinity maturation and somatic hypermutation. B cells upregulate lymphotoxin expression through IL-4Rα signaling; b) A variety of T cells are involved in TLS maintenance, including Th17 cells and Th 9 cells. Th17 cell plasticity permits acquisition of Tfh-like effector characteristics that support germinal center reactions. Th17 cells also initiate TLS formation by remodeling stromal cells. Tfh cells are localized in the B cell follicles expressing high levels of the co-stimulatory molecules such as inducible T cell co-stimulator (ICOS) and IL-21, thereby promoting activation and differentiation of B cells for Ig class switching and Ig production. Th9 cells produce IL-9, levels of which correlate with the degree of inflammatory infiltrate and TLS organization; c) DCs in TLS often show an activated/mature phenotype, with high CD86 and IL-12 expression. DCs increase antigen presentation, form tight clusters with infiltrating CD4⁺ T cells and promote T cell proliferation; d) IL-27 can negatively regulate TLS development by blocking Th17-associated pathology.