Figure 1.

Cellular and molecular signals that control TLS formation. The local accumulation of pro-inflammatory molecules and chemokines promotes the recruitment of LTi cells to the inflammed site promoting their interaction with stromal cells to initiate TLS genesis and cytokine (IL-7, IL-17, RANKL, and LTα1β2) and cytokine receptor (IL-7R, IL-17R, RANK and LTβR) expression. When LTi cells are absent, other immune cells such as macrophages, B lymphocytes and Th17 cells can also interact with stromal cells to induce TLS formation. This interaction culminates in the production of chemokines (CCL19, CCL21, CXCL12 and CXCL13), pro-angiogenic molecules (vascular endothelial growth factors VEGFA and VEGFC) and the expression of adhesion molecules which facilitate the recruitment of additional immune cell types, their retention and organization into the nascent TLS. LTi cells, lymphoid tissue-inducer cells; Th17 cells, T helper cells secreting IL-17; LT, lymphotoxin; RANK, receptor activator of nuclear factor-κB; ICAM, intercellular adhesion molecule 1; VCAM1, Vascular adhesion molecule 1; MADCAM, mucosal vascular addressin cell adhesion molecule 1; VEGFC, vascular endothelial growth factor A/C; IL, interleukin; CCL19: C-C motif chemokine ligand 19; CXCL13, C-X-C motif chemokine ligand 13; HEV, high endothelial venules