The CLEC-2-podoplanin axis controls the contractility of fibroblastic reticular cells and lymph node microarchitecture.

In lymph nodes, fibroblastic reticular cells (FRCs) form a collagen-based reticular network that supports migratory dendritic cells (DCs) and T cells and transports lymph. A hallmark of FRCs is their propensity to contract collagen, yet this function is poorly understood. Here we demonstrate that podoplanin (PDPN) regulates actomyosin contractility in FRCs. Under resting conditions, when FRCs are unlikely to encounter mature DCs expressing the PDPN receptor CLEC-2, PDPN endowed FRCs with contractile function and exerted tension within the reticulum. Upon inflammation, CLEC-2 on mature DCs potently attenuated PDPN-mediated contractility, which resulted in FRC relaxation and reduced tissue stiffness. Disrupting PDPN function altered the homeostasis and spacing of FRCs and T cells, which resulted in an expanded reticular network and enhanced immunity.

B cell homeostasis and follicle confines are governed by fibroblastic reticular cells.

Fibroblastic reticular cells (FRCs) are known to inhabit T cell-rich areas of lymphoid organs, where they function to facilitate interactions between T cells and dendritic cells. However, in vivo manipulation of FRCs has been limited by a dearth of genetic tools that target this lineage. Here, using a mouse model to conditionally ablate FRCs, we demonstrated their indispensable role in antiviral T cell responses. Unexpectedly, loss of FRCs also attenuated humoral immunity due to impaired B cell viability and follicular organization. Follicle-resident FRCs established a favorable niche for B lymphocytes via production of the cytokine BAFF. Thus, our study indicates that adaptive immunity requires an intact FRC network and identifies a subset of FRCs that control B cell homeostasis and follicle identity.

The type 1 diabetes candidate gene Dexi does not affect disease risk in the nonobese diabetic mouse model.

Genome-wide association studies have implicated more than 50 genomic regions in type 1 diabetes (T1D). A T1D region at chromosome 16p13.13 includes the candidate genes CLEC16A and DEXI. Conclusive evidence as to which gene is causal for the disease association of this region is missing. We previously reported that Clec16a deficiency modified immune reactivity and protected against autoimmunity in the nonobese diabetic (NOD) mouse model for T1D. However, the diabetes-associated SNPs at 16p13.13 were described to also impact on DEXI expression and others have argued that DEXI is the causal gene in this disease locus. To help resolve whether DEXI affects disease, we generated Dexi knockout (KO) NOD mice. We found that Dexi deficiency had no effect on the frequency of diabetes. To test for possible interactions between Dexi and Clec16a, we intercrossed Dexi KO and Clec16a knockdown (KD) NOD mice. Dexi KO did not modify the disease protection afforded by Clec16a KD. We conclude that Dexi plays no role in autoimmune diabetes in the NOD model. Our data provide strongly suggestive evidence that CLEC16A, not DEXI, is causal for the T1D association of variants in the 16p13.13 region.