Figure 1.

The initiation, formation and function of TLS. Activated immune cells produce CXCL13 and IL-7, recruit LTi cells to the site of inflammation. LTi cells secrete lymphotoxin (LT) αβ, which binds to lymphotoxin β receptor (LTβR) expressed on local stromal cells, inducing the production of chemokines such as CXCL13, CXCL12, CCL21, and CCL19. These chemokines then trigger the recruitment of lymphocytes, which initiate the development of TLS. The interaction of LTβ and LTβR also leads to the secretion of VEGF, FGF and hepatocyte growth factor (HGF) by stromal cells, as well as the secretion of vascular cell adhesion molecule 1 (VCAM1) and ICAM1. VEGF, FGF, and HGF play a crucial role in promoting the development of high endothelial venules (HEVs), while ICAM and VCAM expressed on local stromal cells facilitate the recruitment of T and B cells from nearby HEVs and promote their eventual organization into TLS. Some local stromal cells differentiate into FDCs upon stimulation with LTα, and FDCs aid in the development and sustenance of TLS by producing chemokines and providing a cellular network that facilitates B cell migration. A subset of CD4+ T cells polarizes into T follicular helper (Tfh, CXCR5^hiPD-1^hiICOS^hi) cells that promote B cell activation and antibody production. TLS facilitate the process of affinity maturation and differentiation of naïve B cells into germinal center B cells and plasma cells that produce antibodies.