Tertiary lymphoid organs, or more properly, tertiary lymphoid tissues (TLTs), are accumulations of lymphoid tissues that arise in situations of chronic inflammation. TLTs have been shown to function like secondary lymphoid tissues (such as peripheral lymph nodes), in the induction of effector B and T cells [1, 2]. Their proximity to the source of antigen, has led to the hypothesis that TLTs generate adaptive immune responses that contribute to disease pathogenesis [1, 2, 3]. In addition, TLTs differ from conventional lymphoid organs in that they are located in ectopic sites , including the meninges.
The lymphotoxin cytokine family, which includes lymphotoxin (LT)-αβ, and the LT-β receptor (LTβR, a member of tumor necrosis factor family), plays an important role for the genesis of secondary lymphoid tissues and TLTs formation. Activation of the LTβR receptor is required for the maturation and homeostasis of stromal cells. Furthermore, overexpression of its ligand LT-αβ led to the TLT formation in the pancreas. Interestingly, LT-αβ and LTβR are upregulated in experimental autoimmune encephalomyelitis (EAE) onset and during subsequent relapses . An interleukin (IL) 17 (IL-17) increase has been observed in different autoimmune diseases, including rheumatoid arthritis, psoriasis, psoriatic arthritis and multiple sclerosis (MS). Previous study also reports that IL-17-producing cells play a critical role driving TLTs in models of chronic inflammation . However the molecular and cellular interaction between IL-17-producing cells and LTβR pathway during meningeal TLTs in MS remain unsolved.
In this issue of Immunity Natalia Pikor and colleagues depict the cellular interactions between T helper 17 cells and LT αβ pathways and their specific role in the meningeal remodeling to propagate neuroinflammation during the early stages of EAE.
Pikor et al. use the animal model of multiple sclerosis [experimental autoimmune encephalomyelitis], which represents an excellent model for studying TLTs formation in vivo. The authors first determine the location and cellular composition of meningeal TLTs. They also provide evidence that proinflammatory Th17 cells first rapidly localized to the meningeal TLTs, followed by B cells. From a cellular point of view, the authors reported that Th17 cell accumulation in meningeal TLTs is associated with destruction of myelin sheaths and astrogliosis during the early stages of EAE.
Pikor et al. further characterize the cellular changes of meningeal stromal cell population. Results from their experiments indicate that Th17 cells induces the formation of a fibroblast reticular cells (FRC)-like stromal cell network that displayed the adhesion molecule (ICAM-1), extracellular matrix molecule component (fibronectin) and an up-regulation of the chemokine CXCL1 into the meninges. The up-regulated chemokine CXCL1, a potent chemoattractant for leukocytes, may thus contribute to the traffic of leukocytes in the meninges, which constitute a portal of leukocyte entry and accumulation in the inflamed CNS.
Chemokines and chemokine receptors are of major importance in guiding immune cells to and within lymphoid tissues. One of the major chemokines shown to be involved in EAE is CCL2 . Deletion of CCL2 or its receptor (CCR2) reduces CNS inflammation and subsequent EAE. In addition, stromal cells were shown to recruit peripheral pro inflammatory Th17 cells by secreting CCL2. Taking into account these aspects, it would have been important to depict the expression of CCL2/CCR2 axis that may participate in chemokine-driven homing of proinflammatory Th17 cells in controlling the development of TLTs. However, no referring to or discussion about the role of the chemokine CCL2/CCR2 axis is present in the text.
What are the mechanisms by which Th17 cells promote meningeal TLTs formation? The authors provide evidence that the cellular and molecular changes of the meningeal fibroblasts in vitro are due to Th17 cells and their soluble mediators, IL-17 and IL-22. In order to confirm the roles of IL-17 and IL-22 in the fibroblast remodeling in vivo, authors inhibit both cytokines via an intracerebroventricular administration of neutralizing antibodies against IL-17 and IL-22. Combined treatment affect B cell zones in meningeal TLTs that correlated with a modest reduction in clinical severity of disease.
The previous study showing that the suppression of EAE and formation of meningeal lymphoid follicles by LTβR -Ig fusion protein  led the authors to better delineate the role of the LTβR pathway for meningeal TLTs maturation and disease progression. The data presented by Pikor et al. provide further support for a relation between LTβR signaling and meningeal TLTs. Interestingly, they elegantly show that LTβR pathway is necessary for the maturation (attractiveness of B cells and deposition of complement within TLTs) but not for the TLT initiation.
It is well known that meningeal space constitutes a principal site for antigen-specific T cell reactivation , however the nature of inflammatory mediators participating in shaping T cell reactivation is still unknown. Pikor demonstrated that, in addition to inducing expression of ECM components and stromal cells remodeling, pro-inflammatory cytokines IL-6, TGF β were increased in meningeal fibroblasts exposed with IL-17 and IL-22. However, in their experiments, the levels of homeostatic lymphoid chemokine CXCL13, CCL19 and CCL21 expression do not change, even though these chemokine have been previously shown to be major player for bronchus-associated lymphoid tissues formation . Again, it would have been interesting to evaluate the levels of CCL2 in these experimental conditions, since it has been reported that exogenous IL-17 increased production of CCL2 in a dose-dependent manner in fibroblasts.
Pikor et al. next hypothesized that Th17 cells, known to induce TLTs neogenesis, could specifically express in vivo LT-αβ, which may play a major role in propagating subsequent Th17 cells responses in the CNS. Results from the experiments indicate that transfer of primed LTB-/- Th17 cells into a WT recipient failed to induced EAA and second that disease-initiating T cells require LT-β expression to facilitate the expression of IL-17 in endogenous cells infiltrating the CNS.
In conclusion, this well designed study clearly demonstrates that the integration of Th17 and LT derived signals initiates meningeal remodeling to propagate neuroinflammation during the early stages of EAE. The results of Pikor et al. shed new light on the formation of meningeal TLTs in chronic inflammation disease. However, the relevance of, and dependence on, these cellular interactions will require follow-up studies. We must keep in mind that TLTs formation may also be beneficial depending on their context. The development of TLTs surrounding established tumors is clearly beneficial under some circumstances. Thus, it could be not excluded that these meningeal TLTs neogenesis in chronic inflammatory disease may constitute an endogenous repair system that may be effectively exploited to resolve inflammation.
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Annabelle Réaux-Le Goazigo, Institut de la Vision, UMR S 968 Inserm/ UPMC/ CNRS 7210, Therapeutic Department, 75012 Paris, France.