Type III interferon drives thymic B cell activation and regulatory T cell generation.

The activation of thymic B cells is critical for their licensing as antigen presenting cells and resulting ability to mediate T cell central tolerance. The processes leading to licensing are still not fully understood. By comparing thymic B cells to activated Peyer's patch B cells at steady state, we found that thymic B cell activation starts during the neonatal period and is characterized by TCR/CD40-dependent activation, followed by immunoglobulin class switch recombination (CSR) without forming germinal centers. Transcriptional analysis also demonstrated a strong interferon signature, which was not apparent in the periphery. Thymic B cell activation and CSR were primarily dependent on type III IFN signaling, and loss of type III IFN receptor in thymic B cells resulted in reduced thymocyte regulatory T cell (Treg) development. Finally, from TCR deep sequencing, we estimate that licensed B cells induce development of a substantial fraction of the Treg cell repertoire. Together, these findings reveal the importance of steady-state type III IFN in generating licensed thymic B cells that induce T cell tolerance to activated B cells.

Sam68 contributes to intestinal inflammation in experimental and human colitis.

Sam68 is an RNA-binding protein with an adaptor role in signal transduction. Our previous work identified critical proinflammatory and apoptotic functions for Sam68, downstream of the TNF/TNFR1 and TLR2/3/4 pathways. Recent studies have shown elevated Sam68 in inflamed tissues from rheumatoid arthritis and ulcerative colitis (UC) patients, suggesting that Sam68 contributes to chronic inflammatory diseases. Here, we hypothesized that deletion of Sam68 is protective against experimental colitis in vivo, via reductions in TNF-associated inflammatory signaling. We used Sam68 knockout (KO) mice to study the role of Sam68 in experimental colitis, including its contributions to TNF-induced inflammatory gene expression in three-dimensional intestinal organoid cultures. We also studied the expression of Sam68 and inflammatory genes in colon tissues of UC patients. Sam68 KO mice treated with an acute course of DSS exhibited significantly less weight loss and histopathological inflammation compared to wild-type controls, suggesting that Sam68 contributes to experimental colitis. Bone marrow transplants showed no pathologic role for hematopoietic cell-specific Sam68, suggesting that non-hematopoietic Sam68 drives intestinal inflammation. Gene expression analyses showed that Sam68 deficiency reduced the expression of proinflammatory genes in colon tissues from DSS-treated mice, as well as TNF-treated three-dimensional colonic organoids. We also found that inflammatory genes, such as TNF, CCR2, CSF2, IL33 and CXCL10, as well as Sam68 protein, were upregulated in inflamed colon tissues of UC patients. This report identifies Sam68 as an important inflammatory driver in response to intestinal epithelial damage, suggesting that targeting Sam68 may hold promise to treat UC patients.

Recently activated CD4 T cells in tuberculosis express OX40 as a target for host-directed immunotherapy.

After Mycobacterium tuberculosis (Mtb) infection, many effector T cells traffic to the lungs, but few become activated. Here we use an antigen receptor reporter mouse (Nur77-GFP) to identify recently activated CD4 T cells in the lungs. These Nur77-GFPHI cells contain expanded TCR clonotypes, have elevated expression of co-stimulatory genes such as Tnfrsf4/OX40, and are functionally more protective than Nur77-GFPLO cells. By contrast, Nur77-GFPLO cells express markers of terminal exhaustion and cytotoxicity, and the trafficking receptor S1pr5, associated with vascular localization. A short course of immunotherapy targeting OX40+ cells transiently expands CD4 T cell numbers and shifts their phenotype towards parenchymal protective cells. Moreover, OX40 agonist immunotherapy decreases the lung bacterial burden and extends host survival, offering an additive benefit to antibiotics. CD4 T cells from the cerebrospinal fluid of humans with HIV-associated tuberculous meningitis commonly express surface OX40 protein, while CD8 T cells do not. Our data thus propose OX40 as a marker of recently activated CD4 T cells at the infection site and a potential target for immunotherapy in tuberculosis.