The TLR4-TRIF pathway can protect against the development of experimental allergic asthma

The Toll-like Receptor (TLR) adaptor proteins Myeloid Differentiating Factor 88 (MyD88) and Toll, interleukin-1 Receptor and Resistance protein (TIR) domain-containing adaptor inducing interferon-β (TRIF) comprise the two principal limbs of the TLR signaling network. We studied the role of these adaptors in the TLR4-dependent inhibition of allergic airway disease and induction of CD4+ICOS+ T cells by nasal application of Protollin™, a mucosal adjuvant composed of TLR2 and 4 agonists. Wild-type (wt), Trif -/- or Myd88 -/- mice were sensitized to birch pollen extract (BPEx), then received intranasal Protollin followed by consecutive BPEx challenges. Protollin's protection against allergic airway disease was TRIF-dependent and MyD88-independent. TRIF-deficiency diminished the CD4+ICOS+ T cell subsets in the lymph nodes draining the nasal mucosa, as well as their recruitment to the lungs. Overall, TRIF-deficiency reduced the proportion of cervical lymph node and lung CD4+ICOS+Foxp3- cells, in particular. Adoptive transfer of cervical lymph node cells supported a role for Protollin-induced CD4+ICOS+ cells in the TRIF-dependent inhibition of AHR. Thus, our data demonstrate that stimulation of the TLR4-TRIF pathway can protect against the development of allergic airway disease and that a TRIF-dependent adjuvant effect on CD4+ICOS+ T cell responses may be a contributing mechanism. This article is protected by copyright. All rights reserved.