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.

Keywords: autoimmunity; cancer; ectopic lymphoid structures; infection; lymphoid neogenesis; rheumatoid arthritis; tertiary lymphoid organs.

Figure 1

Cellular control of lymphoid organ development. (A) LTi cells accumulate at sites of SLO development and secrete lymphotoxin (LT) αβ, which engages the LTβ receptor (LTβR) expressed on stromal LTo cells. LTo cells respond by releasing homeostatic chemokines (CXCL13, CXCL12, CCL21, and CCL19), further recruiting and spatially organizing hematopoietic cells into lymphoid organs. Release of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and hepatocyte growth factor (HGF) by stromal LTo cells promotes the development of high endothelial venules (HEVs). Expression of ICAM and VCAM on fDCs and resident stromal cells further supports leukocyte recruitment. Stromal LTo cells are also capable of differentiating into cell lineages (e.g., follicular DCs) that support SLO development. SLOs are sites for T cell activation and differentiation (e.g., into Th1, Th2, Th17, and Tfh cells). Tfh cells promote the development and maintenance of germinal centers and interact with B cells to generate high-affinity antibodies. (B) In TLO development, immune cells can substitute for conventional cells involved in lymphoid organogenesis. The accumulation of TLO-initiating immune cells at sites of inflammation, and their interaction with tissue resident and stromal cells initiates release of homeostatic chemokines (CXCL13, CXCL12, CCL21, and CCL19) that are involved in the recruitment and spatial organization of cells into TLOs. The plasticity of T cells may contribute to TLO development through the acquisition of Tfh-like effector characteristics that promote B cell activities and antibody generation. As in SLOs, fDCs may support TLO development and maintenance through chemokine production and provide a cellular network for B cell migration. LTi, lymphoid tissue inducer; LTo, lymphoid tissue organizer; ICAM, intracellular adhesion molecule; VCAM, vascular cell adhesion molecule; fDC, follicular dendritic cell.

Figure 2

Novel T cell and innate lymphocyte-derived cytokines associated with TLOs in experimental and human diseases. Due to the crucial role that T cells (blue) and innate lymphocyte populations (green) play in the development of TLOs, a number of their secretory cytokines have been associated with tertiary lymphoneogenesis. Here, we show the cytokines and transcription factors associated with positive (green arrows) and negative (red arrows) control of TLOs. T cell-derived IL-2 and activation of Blimp-1 result in suppression of Bcl-6 expression and inhibition of Tfh differentiation. IL-27 is produced by activated antigen-presenting cells and potently inhibits the development of Th17 cells, which have been linked with TLO development. Experimental and human diseases where these cells have been linked with TLO development are shown. Tfh, T follicular helper cell; Th17, T helper 17 cell; ILC3s, group 3 innate lymphoid cells; NK cell, Natural Killer cell; Treg, regulatory T cell; EAE, experimental autoimmune encephalomyelitis; AIA, antigen-induced arthritis; iBALT, inducible bronchus-associated lymphoid tissue; RA, rheumatoid arthritis; MS, multiple sclerosis; NSCLC, non-small cell lung carcinoma; SG/SS, salivary gland infection displaying Sjögren’s syndrome-like characteristics.

Figure 3

B cells regulate tertiary lymphoid organ development and function. (A) B cells enable TLOs to recapitulate the function of SLOs. Tfh cells support B cell responses in lymphoid organs. The inverse relationship between Blimp-1 and Bcl-6 governs B cell differentiation into memory B cells or immunoglobulin producing plasma cells. In TLOs, the local generation of disease-specific autoantibodies contributes to disease progression. The expression of activation-induced cytidine deaminase (AID) within TLOs marks active class switching and somatic hypermutation that fine-tunes antibody specificity and effector functions. Also, B cells within TLOs can support T cell effector function, including the secretion of IFNγ. (B) B cells can also adopt LTi-like characteristics to promote the development of isolated lymphoid follicles (ILFs) in the small intestine in response to microbiota and dextran sulfate sodium (DSS)-induced colitis. Here, the interaction between B cells and resident stromal cells leads to the production of homeostatic chemokines (CXCL13, CXCL12, CCL21, and CCL19) triggering the recruitment of lymphocytes that initiate lymphoid organ development. Tfh, T follicular helper cell; ACPA/anti-CCP, anti-citrullinated protein antibodies; SSA, Sjögrens syndrome antigen A; SSB, Sjögrens syndrome antigen B; LTαβ, lymphotoxin αβ; LTβR, lymphotoxin β receptor; IFNγ, interferon-γ.