Cryopreservation of mouse thymus depletes thymocytes but supports immune reconstitution on transplantation.

Cryopreservation of mouse thymus depletes donor thymocytes but preserves thymus function when transplanted after thawing into athymic mice. No differences in immune reconstitution were observed between fresh and frozen/thawed transplants suggesting that donor thymocyte depletion does not affect outcome. Thus, cryopreservation of thymus may improve outcomes in thymus transplant patients.

Hedgehog signalling in allograft vasculopathy: a new therapeutic target?

Allograft vasculopathy (AV) leads to chronic rejection of organ transplants, but its causes are obscure. New research from the Jane-Wit laboratory showed that Sonic Hedgehog (SHH) signalling from damaged graft endothelium drives vasculopathy by promoting proinflammatory cytokine production and NLRP3-inflammasome activation in alloreactive CD4PTCH1PD-1T memory cells, offering new diagnostic and therapeutic strategies.

The Pioneer Transcription Factor Foxa2 Modulates T Helper Differentiation to Reduce Mouse Allergic Airway Disease.

Foxa2, a member of the Forkhead box (Fox) family of transcription factors, plays an important role in the regulation of lung function and lung tissue homeostasis. FOXA2 expression is reduced in the lung and airways epithelium of asthmatic patients and in mice absence of Foxa2 from the lung epithelium contributes to airway inflammation and goblet cell hyperplasia. Here we demonstrate a novel role for Foxa2 in the regulation of T helper differentiation and investigate its impact on lung inflammation.

Sonic Hedgehog signalling in the regulation of barrier tissue homeostasis and inflammation.

Epithelial barrier tissues such as the skin and airway form an essential interface between the mammalian host and its external environment. These physical barriers are crucial to prevent damage and disease from environmental insults and allergens. Failure to maintain barrier function against such risks can lead to severe inflammatory disorders, including atopic dermatitis and asthma.

Systemic Pharmacological Smoothened Inhibition Reduces Lung T-Cell Infiltration and Ameliorates Th2 Inflammation in a Mouse Model of Allergic Airway Disease.

Allergic asthma is a common inflammatory airway disease in which Th2 immune response and inflammation are thought to be triggered by inhalation of environmental allergens. Many studies using mouse models and human tissues and genome-wide association have indicated that Sonic Hedgehog (Shh) and the Hedgehog (Hh) signaling pathway are involved in allergic asthma and that Shh is upregulated in the lung on disease induction. We used a papain-induced mouse model of allergic airway inflammation to investigate the impact of systemic pharmacological inhibition of the Hh signal transduction molecule smoothened on allergic airway disease induction and severity.

The pioneer transcription factors Foxa1 and Foxa2 regulate alternative RNA splicing during thymocyte positive selection.

During positive selection at the transition from CD4+CD8+ double-positive (DP) to single-positive (SP) thymocyte, TCR signalling results in appropriate MHC restriction and signals for survival and progression. We show that the pioneer transcription factors Foxa1 and Foxa2 are required to regulate RNA splicing during positive selection of mouse T cells and that Foxa1 and Foxa2 have overlapping/compensatory roles. Conditional deletion of both Foxa1 and Foxa2 from DP thymocytes reduced positive selection and development of CD4SP, CD8SP and peripheral naïve CD4+ T cells.

The transcriptional repressor Bcl6 promotes pre-TCR-induced thymocyte differentiation and attenuates Notch1 activation.

Pre-T-cell receptor (TCR) signal transduction is required for developing thymocytes to differentiate from CD4CD8 double-negative (DN) cell to CD4CD8 double-positive (DP) cell. Notch signalling is required for T-cell fate specification and must be maintained throughout β-selection, but inappropriate Notch activation in DN4 and DP cells is oncogenic. Here, we show that pre-TCR signalling leads to increased expression of the transcriptional repressor and that Bcl6 is required for differentiation to DP.

The IFITM protein family in adaptive immunity.

Interferon-inducible transmembrane (IFITM) proteins are a family of small homologous proteins, localized in the plasma and endolysosomal membranes, which confer cellular resistance to many viruses. In addition, several distinct functions have been associated with different IFITM family members, including germ cell specification (IFITM1-IFITM3), osteoblast function and bone mineralization (IFITM5) and immune functions (IFITM1-3, IFITM6). IFITM1-3 are expressed by T cells and recent experiments have shown that the IFITM proteins are directly involved in adaptive immunity and that they regulate CD4 T helper cell differentiation in a T-cell-intrinsic manner.

Sonic Hedgehog signaling limits atopic dermatitis via Gli2-driven immune regulation.

Hedgehog (Hh) proteins regulate development and tissue homeostasis, but their role in atopic dermatitis (AD) remains unknown. We found that on induction of mouse AD, Sonic Hedgehog (Shh) expression in skin, and Hh pathway action in skin T cells were increased. Shh signaling reduced AD pathology and the levels of Shh expression determined disease severity.

IFITM proteins drive type 2 T helper cell differentiation and exacerbate allergic airway inflammation.

The interferon-inducible transmembrane (Ifitm/Fragilis) genes encode homologous proteins that are induced by IFNs. Here, we show that IFITM proteins regulate murine CD4 Th cell differentiation. Ifitm2 and Ifitm3 are expressed in wild-type (WT) CD4 T cells.

Foxa1 and Foxa2 in thymic epithelial cells (TEC) regulate medullary TEC and regulatory T-cell maturation.

The Foxa1 and Foxa2 transcription factors are essential for mouse development. Here we show that they are expressed in thymic epithelial cells (TEC) where they regulate TEC development and function, with important consequences for T-cell development. TEC are essential for T-cell differentiation, lineage decisions and repertoire selection.

Gli3 in fetal thymic epithelial cells promotes thymocyte positive selection and differentiation by repression of .

Gli3 is a Hedgehog (Hh)-responsive transcription factor that can function as a transcriptional repressor or activator. We show that Gli3 activity in mouse thymic epithelial cells (TECs) promotes positive selection and differentiation from CD4 CD8 to CD4 CD8 single-positive (SP4) cells in the fetal thymus and that Gli3 represses Constitutive deletion of , and conditional deletion of from TECs, reduced differentiation to SP4, whereas conditional deletion of from thymocytes did not. Conditional deletion of from TECs increased differentiation to SP4, and expression of Shh was upregulated in the Gli3-deficient thymus.

Frontline Science: Shh production and Gli signaling is activated in vivo in lung, enhancing the Th2 response during a murine model of allergic asthma.

The pathophysiology of allergic asthma is driven by Th2 immune responses after aeroallergen inhalation. The mechanisms that initiate, potentiate, and regulate airway allergy are incompletely characterized. We have shown that Hh signaling to T cells, via downstream Gli transcription factors, enhances T cell conversion to a Th2 phenotype.