Th17 Cells Induce Ectopic Lymphoid Follicles in Central Nervous System Tissue Inflammation

Abstract

SUMMARY Ectopic lymphoid follicles are hallmarks of chronic autoimmune inflammatory diseases such as multiple sclerosis (MS), rheumatoid arthritis, Sjögren’s syndrome, and myasthenia gravis. However, the effector cells and mechanisms that induce their development are unknown. Here we showed that in experimental autoimmune encephalomyelitis (EAE), the animal model of MS, Th17 cells specifically induced ectopic lymphoid follicles in the central nervous system (CNS). Development of ectopic lymphoid follicles was partly dependent on the cytokine interleukin 17 (IL-17) and on the cell surface molecule Podoplanin (Pdp), which was expressed on Th17 cells, but not on other effector T cell subsets. Pdp was also crucial for the development of secondary lymphoid structures: Pdp-deficient mice lacked peripheral lymph nodes and had a defect in forming normal lymphoid follicles and germinal centers in spleen and lymph node remnants. Thus, Th17 cells are uniquely endowed to induce tissue inflammation, characterized by ectopic lymphoid follicles within the target organ.

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

“…This demonstrates the ability of this effector T helper cell to initiate ELF development. Notably, the adoptive transfer of in vitro generated Th17 cells into mice is also sufficient to drive ELF development in a model of multiple sclerosis 19. The expression of the cell surface glycoprotein podoplanin (also called gp38) by Th17 cells was required for the development of these lymphoid follicles in the central nervous system.…”

“…The expression of the cell surface glycoprotein podoplanin (also called gp38) by Th17 cells was required for the development of these lymphoid follicles in the central nervous system. Indeed, mice deficient in podoplanin, or its receptor CLEC‐2, display a defect in the development and maintenance of lymph nodes 13, 19, 20. Our recent study of synovial ELF development in IL‐27R‐deficient mice with inflammatory arthritis identified podoplanin‐expressing T cells within synovial lymphoid aggregates and described IL‐27 as a negative regulator of podoplanin‐expressing Th17 cells 21…”

“…Plasticity among effector T helper cells may also contribute to ELF development. For example, Th17 cells are linked with ELF development in the central nervous system, lungs and inflamed joint tissue 18, 19, 21. Interestingly, in the central nervous system Th17 cells develop a ‘Tfh‐like’ phenotype that may contribute to ELF development and function 19.…”

Hyperactive gp130/STAT3‐driven gastric tumourigenesis promotes submucosal tertiary lymphoid structure development

“…1 d ). TLSs also contained podoplanin (Pdpn; also called gp38) expressing cells, marking the presence of stromal cells required for lymphoid organ development, and the support of lymphocyte migration and antigen presentation4, 35 (Fig. 1 d ).…”

“…This T cell subset, and its signature cytokine IL‐17, has been associated with TLS development in infection, autoimmunity, allograft rejection and cancer 4, 35, 39, 40, 41. Nevertheless, a role for Th17/IL‐17 in TLS development remains controversial and is likely disease‐ and context‐dependent.…”