A Novel Role for Hedgehog in T-Cell Receptor Signaling: Implications for Development and Immunity

Abstract

The Hedgehog (Hh) signaling pathway is a key regulator of both embryonic development and homeostasis of adult tissues, including thymus and blood. In the thymus, Hh signals for differentiation, survival and proliferation in the early stages of T cell development, before TCR gene rearrangement. Our recent data has shown that Hh signaling also modulates T cell receptor (TCR) signal strength in more mature T lineage cells. We showed that constitutive activation of the Hh pathway in thymocytes (by transgenic expression of the transcriptional activator form of Gli2) decreased TCR signal strength with profound consequences for the thymus-allowing self-reactive T cells to escape deletion and altering T cell CD4/CD8 lineage decisions. In contrast, in the Sonic Hh deficient thymus, TCR signaling was increased, again influencing both TCR repertoire selection and CD4/8 lineage commitment. In peripheral T cells, the transcriptional changes induced by activation of the Hh signaling pathway lead to reduced T cell activation. Hh signaling also attenuated ERK phosphorylation and proliferation in mature T cells on TCR ligation. Modulation of TCR signal strength by Hh pathway activation has importance for immunity as the presence or absence of Hh in the environment in which a T cell is activated would shape the immune response.

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

“…As our findings were in contrast to several other reports describing an influence of Hh signaling on the transition from the double-positive (DP) to the single-positive (SP) stage of thymocyte development [22], [23], [24], we decided to repeat the analyses with mice backcrossed to the C57BL/6 background. Although the overall thymic cellularity (Figure 1A) and the percentages of double-negative (DN) thymocytes (Figure 1B,C) were similar in both genotypes, we found that the relative number of DP thymocytes was increased in Ptch flox/flox CD4Cre +/− mutant mice while the percentages of CD4 and CD8 SP thymocytes were decreased (Figure 1C).…”

Role of endogenous Annexin-A1 in the regulation of thymocyte positive and negative selection

“…30 Studies of the MAPK cascades activated during positive and negative selection have indicated that positively selected ligands induce a slow and sustained accumulation of Erk activity; in contrast, ligands that induce negative selection provoke a strong and transient burst of Erk phosphorylation. [31][32][33][34] Here we show that stimulation of AnxA1 -/-thymocytes with anti-CD3 caused a delayed and weaker phosphorylation of Erk1/2 compared to their NFκB than CD4 SP cells; and, furthermore, activation of this transcription factor determines the threshold of signalling responsible for positive and negative selection of MHC class I-restricted CD8 cells. [38][39][40] Our analysis of female HY-TCR/AnxA1 -/-thymocytes shows a significant impairment in the development of CD8 SP cells suggesting that reduced activation of NFκB in these cells might, at least, contribute to this phenotype.…”

Hedgehog Pathway Inhibitors Promote Adaptive Immune Responses in Basal Cell Carcinoma

“…T-cell activation requires both T-cell receptor (TCR) and costimulatory molecule ligation by professional antigen-presenting cells (APC), and the outcome of the stimulatory signal is influenced by the microenvironment of the T cell and the APC. The Hh signaling pathway reduced the strength of the TCR signal in mature peripheral T cells (18,19). In addition, the repression of the Hh signaling pathway in T cells increased T-cell activation (20).…”