Faculty Bibliography

OBJECTIVE:The intestinal microbiota has been associated with the development of inflammatory arthritis. The aim of this study was to dissect intestinal mucosal immune responses in the preclinical phase of arthritis and determine the requirement of Th17 cells, beyond the cytokine interleukin-17 (IL-17), for arthritis development. We further examined whether the involvement of Th17 cells in arthritis depends on the host microbiota. METHODS:) mice, and assessed the impact of microbiota on the Th17-dependence of CIA. RESULTS: mice showed a specific reduction of mucosal Th17 and partially reduced IL-17-producing CD8 T cells. However, total levels of IL-17A, mostly produced by γδ T cells and neutrophils, were unaffected. Arthritis was significantly reduced in Th17-deficient mice, suggesting additional IL-17A-independent roles for Th17 cells. Accordingly, antigen-stimulated T cells from Th17-deficient mice produced less IL-17A, IL-17F and GM-CSF. Importantly, Th17-dependence of arthritis was lost upon substitution of intestinal microbiota. CONCLUSION/CONCLUSIONS:These data suggest that activation of mucosal immunity precedes arthritis development, and support a microbiota-dependent role for Th17 cells in arthritis. Therefore, a microbiome-guided stratification of patients might improve the efficacy of Th17-targeted therapies.

Deficient expression of Suppressor Special AT-rich Binding-1 (SATB1) hampers thymocyte development and results in inept T cell lineages. Recent data implicate dysregulated SATB1 expression in the pathogenesis of mycosis fungoides (MF), the most frequent variant of cutaneous T cell lymphoma (CTCL). Here we report on a disease-stage-associated decrease of SATB1 expression and an inverse expression of STAT5 and SATB1 in situ. Importantly, STAT5 inhibited SATB1 expression through induction of miR-155. Decreased SATB1 expression triggered enhanced expression of IL-5 and IL-9 (but not IL-6 and IL-32) whereas increased SATB1 expression had the opposite effect indicating that the mir-155 target SATB1 is a repressor of IL-5 and IL-9 in malignant T cells. In accordance, inhibition of STAT5, and its upstream activator Janus Kinase-3 (Jak3), triggered increased SATB1 expression and a concomitant suppression of IL-5 and IL-9 expression in malignant T cells. In conclusion, we provide a mechanistic link between the proto-oncogenic Jak3/STAT5/miR-155 pathway, SATB1, and cytokines linked to CTCL severity and progression indicating that SATB1 dysregulation is involved in CTCL pathogenesis.

OBJECTIVE:CD4Cre mice, and investigate the role of Th17 cytokines in the disease pathogenesis. METHODS:CD4Cre mice onto an IL-22 knockout background or treating them with a neutralizing antibody against IL-17, we interrogated how these Th17 cytokines contribute to disease pathogenesis. RESULTS:CD4Cre mice, revealing a central role of Th17 cells in the regulation of OCP numbers and RANKL expression on stromal cells. CONCLUSION/CONCLUSIONS:CD4Cre mice, leading to cutaneous and synovio-entheseal inflammation, and bone pathology highly reminiscent of psoriatic arthritis. Both IL-17A and IL-22 produced by Th17 cells play critical roles in promoting the cutaneous and musculoskeletal inflammation that characterizes psoriatic arthritis..

Cutaneous T cell lymphoma is a heterogeneous group of lymphomas characterized by the accumulation of malignant T cells in the skin. The molecular and cellular etiology of this malignancy remains enigmatic and what role antigenic stimulation plays in the initiation and/or progression of the disease remains to be elucidated. Deep sequencing of the tumor genome revealed a highly heterogeneous landscape of genetic perturbations and transcriptome analysis of transformed T cells further highlighted the heterogeneity of this disease. Nonetheless, using data harvested from high-throughput transcriptional profiling allowed us to develop a reliable signature of this malignancy. Focusing on a key cytokine signaling pathway, previously implicated in CTCL pathogenesis, JAK/STAT signaling, we used conditional gene targeting to develop a fully penetrant small animal model of this disease that recapitulates many key features of mycosis fungoides, a common variant of CTCL. Using this mouse model, we demonstrate that T cell receptor engagement is critical for malignant transformation of the T lymphocytes and that progression of the disease is dependent on microbiota.

CD4⁺ T cells are tightly regulated by microbiota in the intestine, but whether intestinal T cells interface with host-derived metabolites is less clear. Here, we show that CD4⁺ T effector (Teff) cells upregulated the xenobiotic transporter, Mdr1, in the ileum to maintain homeostasis in the presence of bile acids. Whereas wild-type Teff cells upregulated Mdr1 in the ileum, those lacking Mdr1 displayed mucosal dysfunction and induced Crohn's disease-like ileitis following transfer into Rag1^-/- hosts. Mdr1 mitigated oxidative stress and enforced homeostasis in Teff cells exposed to conjugated bile acids (CBAs), a class of liver-derived emulsifying agents that actively circulate through the ileal mucosa. Blocking ileal CBA reabsorption in transferred Rag1^-/- mice restored Mdr1-deficient Teff cell homeostasis and attenuated ileitis. Further, a subset of ileal Crohn's disease patients displayed MDR1 loss of function. Together, these results suggest that coordinated interaction between mucosal Teff cells and CBAs in the ileum regulate intestinal immune homeostasis.

B lymphocytes are essential for an efficient immune response against a variety of pathogens. A large fraction of hematologic malignancies is of B cell origin, suggesting that the development and activation of B cells need to be tightly regulated. In recent years, increasing evidence has emerged demonstrating that microRNAs (miRNAs) - a class of non-coding RNAs that control gene expression - are involved in the regulation of B cell development and function. We provide here an overview of the current knowledge on the role of miRNAs and their relevant targets in B cell development, B cell activation, and B cell malignant transformation.

B cell development is a tightly regulated process dependent on sequential rearrangements of immunoglobulin loci that encode the antigen receptor. To elucidate the role of microRNAs (miRNAs) in the orchestration of B cell development, we ablated all miRNAs at the earliest stage of B cell development by conditionally targeting the enzymes critical for RNAi in early B cell precursors. Absence of any one of these enzymes led to a block at the pro- to pre-B cell transition due to increased apoptosis and a failure of pre-B cells to proliferate. Expression of a Bcl2 transgene allowed for partial rescue of B cell development, however, the majority of the rescued B cells had low surface immunoglobulin expression with evidence of ongoing light chain editing. Our analysis revealed that miRNAs are critical for the regulation of the PTEN-AKT-FOXO1 pathway that in turn controls Rag expression during B cell development.