Figure 1.

Tertiary lymphoid organ (TLO) initiation and formation. (A) TLO-initiating immune cells [among which are lymphoid tissue inducer (LTi)-like cells] accumulate at sites of inflammation and interact with stromal mesenchymal lymphoid tissue organizing (LTo) cells. The binding of LTα₁β₂ on LTi cells with LTβR on LTo cell leads to the release of chemokines CCL19, CCL21, and CXC-chemokine ligand 13 (CXCL13) that mediate further immune cell recruitment and spatial organization within the forming TLO. (B) Similarly, local release of homeostatic chemokines drives the formation of high endothelial venules (HEVs) and lymphangiogenesis, leading to homing of (auto-or alloreactive) naïve and memory B and T cells. A well-organized TLO is composed of compartmentalized T and B cell areas, follicular dendritic cells (FDC), dendritic cells, HEVs, and lymphatic vessels. (C) Under the influence of LTα₁β₂, stromal cells acquire the phenotypic and functional properties of FDCs, which facilitate persistent antigen presentation within TLOs, and CD4⁺ T cells acquire follicular helper (T_FH)-like effector characteristics (CXCR5^hiPD-1^hiICOS^hi) to drive activation of B cells. Cytokines, such as B-cell-activating factor (BAFF), IL-21, and IL-6, contribute to the survival and maintenance of T_FH cells and germinal center (GC) B cells, which subsequently differentiate into antibody-secreting plasma cells.