ICOS-expressing CD4 T cells induced via TLR4 in the nasal mucosa are capable of inhibiting experimental allergic asthma.
Modulation of adaptive immune responses via the innate immune pattern recognition receptors, such as the TLRs, is an emerging strategy for vaccine development. We investigated whether nasal rather than intrapulmonary application of Protollin, a mucosal adjuvant composed of TLR2 and TLR4 ligands, is sufficient to elicit protection against murine allergic lower airway disease. Wild-type, Tlr2(-/-), or Tlr4(-/-) BALB/c mice were sensitized to a birch pollen allergen extract (BPEx), then received either intranasal or intrapulmonary administrations of Protollin or Protollin admixed with BPEx, followed by consecutive daily BPEx challenges. Nasal application of Protollin or Protollin admixed with BPEx was sufficient to inhibit allergic lower airway disease with minimal collateral lung inflammation. Inhibition was dependent on TLR4 and was associated with the induction of ICOS in cells of the nasal mucosa and on both CD4+Foxp3+ and CD4+Foxp3- T cells of the draining lymph nodes (LNs), as well as their recruitment to the lungs. Adoptive transfer of cervical LN CD4+ICOS+, but not CD4+ICOS-, cells inhibited BPEx-induced airway hyperresponsiveness and bronchoalveolar lavage eosinophilia. Thus, our data indicate that expansion of resident ICOS-expressing CD4+ T cells of the cervical LNs by nasal mucosal TLR4 stimulation may inhibit the development of allergic lower airway disease in mice.
Meakins-Christie Laboratories, Department of Medicine, McGill University and McGill University Health Centre Research Institute, Montreal, Quebec H2X 2P2, Canada.
Karim H
KH
Shalaby
Taisuke
T
Jo
Emily
E
Nakada
Alexandra
A
Allard-Coutu
Kimitake
K
Tsuchiya
Nobuaki
N
Hirota
Salman T
ST
Qureshi
Karim
K
Maghni
Clément R
CR
Rioux
James G
JG
Martin
D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control*; D029662:Betula / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D005260:Female; D060889:Inducible T-Cell Co-Stimulator Protein / Q000096:biosynthesis*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009297:Nasal Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011058:Pollen / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000502:physiology*
C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4