MHCII-restricted antigen presentation by lymph node stromal cells is essential for regulatory T-cell proliferation and functions, and for the regulation of autoimmunity.

Several solid malignancies trigger lymphangiogenesis, facilitating metastasis. Tumor-associated lymphatic vessels significantly contribute to the generation of an immunosuppressive tumor microenvironment (TME). Here, we have investigated the ability of tumoral lymphatic endothelial cells (LEC) to function as MHC class II-restricted antigen-presenting cells in the regulation of antitumor immunity. Using murine models of lymphangiogenic tumors engrafted under the skin, we have shown that tumoral LECs upregulate MHC class II and the MHC class II antigen-processing machinery, and that they promote regulatory T-cell (Treg) expansion ex vivo. In mice with LECrestricted lack of MHC class II expression, tumor growth was severely impaired, whereas tumor-infiltrating effector T cells were increased. Reduction of tumor growth and reinvigoration of tumor-specific T-cell responses both resulted from alterations of the tumor-infiltrating Treg transcriptome and phenotype. Treg-suppressive functions were profoundly altered in tumors lacking MHC class II in LECs. No difference in effector T-cell responses or Treg phenotype and functions was observed in tumor-draining lymph nodes, indicating that MHC class IIrestricted antigen presentation by LECs was required locally in the TME to confer potent suppressive functions to Tregs. Altogether, our study suggests that MHC class II-restricted antigen-presenting tumoral LECs function as a local brake, dampening T cell-mediated antitumor immunity and promoting intratumoral Treg-suppressive functions.

Regulatory T cells (Tregs) play a crucial role in controlling autoimmune and inflammatory responses. Recent studies have demonstrated that dendritic cells (DCs) contribute to the homeostasis of peripheral Tregs. Autophagy, a critical pathway for cellular homeostasis, is active in DCs and is upregulated in different inflammatory conditions. We have shown that Tregs are expanded and have phenotypic alterations and impaired suppressive functions in mice with autophagy-deficient DCs. RNA profiling of Tregs revealed that autophagy in DCs is required to stabilize Treg expression signatures. This phenotype is linked to the downregulation of ICOS-Ligand expression in autophagy-deficient DCs, a consequence of the accumulation of ADAM10, the metalloproteinase responsible for its cleavage. Upon inflammation, in antigen-induced arthritis, mice with autophagy-deficient DCs exhibit increased synovial inflammation and cartilage and bone erosion correlating with Treg-to-Th17 conversion. Our data reveal a mechanism that couples autophagy deficiency in DCs to the function, homeostasis, and stability of Tregs.

Lymphatic endothelial cells (LECs) present peripheral tissue antigens to induce T cell tolerance. In addition, LECs are the main source of sphingosine-1-phosphate (S1P), promoting naive T cell survival and effector T cell exit from lymph nodes (LNs). Autophagy is a physiological process essential for cellular homeostasis. We investigated whether autophagy in LECs modulates T cell activation in experimental arthritis. Whereas genetic abrogation of autophagy in LECs does not alter immune homeostasis, it induces alterations of the regulatory T cell (T reg cell) population in LNs from arthritic mice, which might be linked to MHCII-mediated antigen presentation by LECs. Furthermore, inflammation-induced autophagy in LECs promotes the degradation of Sphingosine kinase 1 (SphK1), resulting in decreased S1P production. Consequently, in arthritic mice lacking autophagy in LECs, pathogenic Th17 cell migration toward LEC-derived S1P gradients and egress from LNs are enhanced, as well as infiltration of inflamed joints, resulting in exacerbated arthritis. Our results highlight the autophagy pathway as an important regulator of LEC immunomodulatory functions in inflammatory conditions.

Stromal cells (SCs) are strategically positioned in both lymphoid and nonlymphoid organs to provide a scaffold and orchestrate immunity by modulating immune cell maturation, migration and activation. Recent characterizations of SCs have expanded our understanding of their heterogeneity and suggested a functional specialization of distinct SC subsets, further modulated by the microenvironment. Lymph node SCs (LNSCs) have been shown to be particularly important in maintaining immune homeostasis and T cell tolerance. Under inflammation situations, such as viral infections or tumor development, SCs undergo profound changes in their numbers and phenotype and play important roles in contributing to either the activation or the control of T cell immunity. In this review, we highlight the role of SCs located in LNs in shaping peripheral T cell responses in different immune contexts, such as autoimmunity, viral and cancer immunity.

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Chronic stress is now recognized as a risk factor for disease development and/or exacerbation. It has been shown to affect negatively the immune system and notably the humoral immune response. Corticotropin-releasing hormone (CRH) is known to play a crucial role in stress response. CRH receptors are expressed on different immune cells such as granulocytes, monocytes and T cells. However, up to now, no CRH receptor has been described on B cells which are key players of the humoral immune response. In order to highlight new pathways by which stress may impact immunity, we investigated the role of CRH in B cells. Here we show that splenic B cells express the CRH receptor 2 (CRHR2), but not CRHR1. This receptor is functional since CRH treatment of B cells activates different signaling pathways (e.g. p38) and decreases B cell viability. Finally, we show that immunization of mice with two types of antigens induces a more intense CRHR staining in secondary lymphoid organs where B cells are known to respond to the antigen. Altogether our results demonstrate, for the first time, that CRH is able to modulate directly B cell activity through the presence of CRHR2.

Glucocorticoids are involved in the developing brain but, in excessive amounts, may depress its growth and cause psychomotor development disorders. To test the long-term vulnerability of motor structures such as the cerebellum to supraphysiological corticosterone (CORT), the hormone was subcutaneously delivered at a dose of 20 mg/kg from postnatal day (P) 8 to P29 in C57BL/6 male mice evaluated for sensorimotor functions at P15, P22, P29, and 3 months. Relative to placebo, CORT increased motor activity in the open-field at P29 and 3 months as well as facilitating rotorod acquisition and visuomotor control necessary for swimming towards a visible goal without affecting spatial learning in the Morris water maze. CORT caused lobulespecific effects on cerebellar morphology by decreasing granule cell layer thickness in simplex lobule but increasing molecular and granule cell layer thickness in crus 2. The functional impact of these changes is indicated by significant correlations found between cerebellar size and activity levels or proficiency on the rotorod test of motor coordination.