In Brief

Signalling

Integrated regulation of Toll-like receptor responses by Notch and interferon-γ pathways Hu, X. et al. Immunity 29 Oct 2008 (doi: 10.1016/j.immuni.2008.08.016)

Signalling pathways downstream of Toll-like receptor (TLR) activation are tightly regulated to allow fine-tuning of innate immune-cell responses and to prevent uncontrolled inflammation. Here, Ivashkiv and colleagues define a new feedback inhibitory pathway of TLR signalling in human and mouse macrophages. They show that maximal expression of Notch proteins, including the transcriptional repressors HES1 and HEY1, downstream of TLR triggering requires the activation of both TLR and Notch signalling pathways. In turn, HES1 and HEY1 attenuate TLR-induced expression of pro-inflammatory cytokines. Interferon-γ, which is known to influence cellular responses following TLR signalling, inhibits this negative feedback loop by targeting the Notch pathway. So, the integration of Notch and TLR signalling pathways underlies fine-tuning of innate immune responses.

Immunotherapy

Specific immunosuppression with inducible Foxp3-transduced polyclonal T cells Andersen, K. G., Butcher, T. & Betz, A. G. PLoS Biol. 11, e276 (2008)

One approach to induce immune tolerance for the treatment of autoimmune diseases aims to generate conventional T cells that have the suppressive activity of regulatory T cells through the ectopic expression of forkhead box P3 (FOXP3). Andersen and colleagues generated conventional CD4⁺ T cells transduced with an inducible form of FOXP3 (iFOXP3) that is constitutively expressed but is only functional following induction. These cells homed as usual to peripheral lymph nodes in mice following adoptive transfer and then underwent antigen-specific clonal expansion, suggesting their participation in an antigen-specific response. Following the functional activation of iFOXP3, these cells adopted a regulatory T-cell phenotype and selectively suppressed the immune response in which they were initially involved. Transfer of these cells also suppressed established collagen-induced arthritis. So, this study provides a strategy to selectively suppress an ongoing immune response, without previous knowledge of the antigens that are involved.

Regulatory T cells

CD4⁺CD25⁺ Tregs control the TRAIL-dependent cytotoxicity of tumor-infiltrating DCs in rodent models of colon cancer Roux, S. et al. J. Clin. Invest. 118, 3751–3761 (2008)

This study describes another way in which regulatory T (T_Reg) cells might interfere with immune responses, in this case by inhibiting the cytotoxic activity of tumour-infiltrating dendritic cells (DCs). A combination of two treatments that are used in the clinic — cyclophosphamide (which depletes T_Reg cells) and Mycobacterium bovis bacillus Calmette–Guérin (BCG) — led to tumour regression in two rat cancer models. The antitumour effect was associated with decreased numbers of T_Reg cells and a large infiltration of CD11b⁺ DCs, which killed tumour cells in a TRAIL (TNF-related apoptosis-inducing ligand)-dependent manner. Upregulation of TRAIL expression by the CD11b⁺ DCs required BCG-mediated Toll-like receptor signalling and was abrogated in mice that received the combination therapy together with transferred T_Reg cells. This suggests that T_Reg cells control the capacity of BCG to confer cytotoxic ability on tumour-infiltrating DCs.