Regulatory T cells contribute to allergen tolerance induced by daily airway immunostimulant exposures.
Endotoxin and other immunostimulants ubiquitous in ambient air are potent mucosal adjuvants, yet only a minority of individuals develop aeroallergen hypersensitivities, whereas the majority develop tolerance. These investigations were performed to reconcile this paradox. During initial experiments, mice received a primary series of weekly intranasal OVA immunizations (1(0) vaccination). Selected mice also received intranasal sterile house dust extract (HDE) with each OVA vaccination, at a dose previously found to exert adjuvant activity. A third group of OVA-vaccinated mice received intranasal HDE on a daily basis, but at one seventh the adjuvant dose, beginning 1 week before the first and ending with the last 1(0) OVA vaccination. Mice were then left untreated for 4 weeks, and then received a secondary series of weekly intranasal OVA immunizations with adjuvant doses of HDE (2(0) sensitization). Three weeks later, OVA-specific airway challenges and immune responses were assessed. Analogous experiments were conducted with LPS. Mice receiving daily intranasal HDE or LPS during 1(0) OVA vaccination were highly resistant to 2(0) sensitization, whereas the mice in other experimental groups readily developed Th2-biased airway hypersensitivity. Tolerance was associated with poor OVA-specific CD4 cell proliferation and with local natural T-regulatory cell (Treg) expansion. Finally, Treg depletion by delivery of the anti-CD25 monoclonal antibody during 1(0) vaccination attenuated the tolerogenic effects of daily airway HDE exposures. These studies suggest that regular airway immunostimulant exposures selectively increase local Treg numbers and activity in an antigen-independent manner, thereby promoting the development of aeroallergen tolerance.
Lee
Steve M
SM
Department of Medicine, University of California at San Diego, La Jolla, 92093-0663, USA.
Batzer
Glenda
G
Ng
Nicholas
N
Lam
Diane
D
Pattar
Sundeep S
SS
Patel
Neal D
ND
Horner
Anthony A
AA
D000485:Allergens / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D004391:Dust; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D007108:Immune Tolerance / Q000276:immunology*; D007073:Immunoglobulin E / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012130:Respiratory Hypersensitivity / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D014612:Vaccines
D000485:Allergens; D000911:Antibodies, Monoclonal; D004391:Dust; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D008070:Lipopolysaccharides; D014612:Vaccines; D007073:Immunoglobulin E
Immunity. 2008 Jul 18;29(1):114-26
18617425
Am J Ind Med. 2006 Jun;49(6):474-91
16586405
J Exp Med. 2006 Mar 20;203(3):777-88
16533885
J Allergy Clin Immunol. 2001 May;107(5):790-6
11344344
J Exp Med. 2003 Feb 17;197(4):403-11
12591899
Immunology. 2008 Dec;125(4):450-8
19128356
Am J Respir Crit Care Med. 2002 Oct 1;166(7):939-44
12359650
J Immunol. 2003 Apr 1;170(7):3898-905
12646659
N Engl J Med. 2002 Sep 19;347(12):869-77
12239255
Springer Semin Immunopathol. 2006 Aug;28(1):41-50
16874537
J Allergy Clin Immunol. 2005 Nov;116(5):1053-7
16275375
J Allergy Clin Immunol. 2006 Jun;117(6):1396-403
16751003
J Clin Invest. 2005 Jul;115(7):1923-33
15937545
J Immunol. 2005 Feb 15;174(4):2412-9
15699178
Semin Immunopathol. 2008 Feb;30(1):53-62
17989979
J Exp Med. 2002 Dec 16;196(12):1645-51
12486107
J Allergy Clin Immunol. 2006 Aug;118(2):354-60
16890758
Indoor Air. 2008 Dec;18(6):480-7
19120498
J Allergy Clin Immunol. 2004 Mar;113(3):448-54
15007346
J Allergy Clin Immunol. 2005 Jul;116(1):185-91
15990793
Nat Immunol. 2005 Mar;6(3):223-6
15716966
J Immunol. 2007 Mar 1;178(5):2961-72
17312141
J Clin Invest. 2006 Feb;116(2):485-94
16424940
J Allergy Clin Immunol. 2006 May;117(5):1133-40
16675343
J Allergy Clin Immunol. 2006 May;117(5):1074-81
16675335
J Immunol. 2008 Aug 15;181(4):2925-32
18684984
J Immunol. 2008 Nov 1;181(9):6456-66
18941236
Cell Immunol. 1998 Nov 25;190(1):77-82
9826449