The Hedgehog Receptor Patched1 in T Cells Is Dispensable for Adaptive Immunity in Mice

Abstract

Hedgehog (Hh) signaling modulates T cell development and function but its exact role remains a matter of debate. To further address this issue we made use of conditional knock-out mice in which the Hh receptor Patched1 (Ptch) is inactivated in the T cell lineage. Thymocyte development was moderately compromised by the deletion of Ptch as characterized by reduced numbers of CD4 and CD8 single-positive cells. In contrast, peripheral T cells were not affected. Proliferation and IFNγ secretion by Ptch-deficient T cells were indistinguishable from controls irrespectively of whether we used strong or suboptimal conditions for stimulation. Analysis of CTL and Treg cell functions did not reveal any differences between both genotypes, and T cell apoptosis induced by glucocorticoids or γ-irradiation was also similar. Surprisingly, absence of Ptch did not lead to an activation of canonic Hh signaling in peripheral T cells as indicated by unaltered expression levels of Gli1 and Gli2. To test whether we could uncover any role of Ptch in T cells in vivo we subjected the mutant mice to three different disease models, namely allogeneic bone marrow transplantation mimicking graft-versus-host disease, allergic airway inflammation as a model of asthma and growth of adoptively transferred melanoma cells as a means to test tumor surveillance by the immune system. Nonetheless, we were neither able to demonstrate any difference in the disease courses nor in any pathogenic parameter in these three models of adaptive immunity. We therefore conclude that the Hh receptor Ptch is dispensable for T cell function in vitro as well as in vivo.

Altered hematopoietic system and self-tolerance in Bardet-Biedl Syndrome

“…Interestingly, Ift20 ablation at later stages of T-cell development using Cd4-Cre had only mild effect on the T-cell maturation [15,67]. Similar findings were shown using Lck-Cre and Cd4-Cre driven ablation of SMO, a receptor involved in SHH signaling [24,68]. In our study, the T-cell lineage was largely unaffected in the Bbs4 KO/KO mouse and in Cd4-Cre driven Bbs4 cKO/cKO mice, which suggests that the BBSome is dispensable for SHH signaling in thymocytes and for T-cell development in general.…”

Airway Epithelial Cells Are Crucial Targets of Glucocorticoids in a Mouse Model of Allergic Asthma

“…Allergic airway inflammation (AAI) was induced in mice using chicken egg OVA, as previously described (26), and served as a model of allergic asthma (27). Mice were sensitized on days 0, 7, 14, and 21 by i.p.…”

“…BALF was obtained by cannulation of the trachea and flushing the lung three times with 1 ml of 0.1% BSA (26). Prior to Ab staining, BALF was treated with erythrocyte lysis buffer (20 mM Tris/HCl, 155 mM NH 4 Cl [pH = 7.2]).…”

“…Flat-bottom 96-well plates were coated with 50 mg/ml OVA in 0.1 M Na 2 CO 3 (pH = 9.5) overnight at 4˚C (26). After washing with 0.05% Tween-20 and blocking with 10% FCS for 1 h, serum samples were added to the plate and incubated for 1 d at 4˚C.…”

Cancer stem cells as targets for immunotherapy

“…20 Hh signalling is relevant in immune cell development and function, although its effect on peripheral T-cell function is controversial. [21][22][23][24] Because it is also involved in myeloid-derived suppressor cell (MDSC) function, 25 Hh inhibitors may deliver additional benefits.…”