Regulatory CD4+Foxp3+ T cells control the severity of anaphylaxis.
OBJECTIVE
Anaphylaxis is a life-threatening outcome of immediate-type hypersensitivity to allergen, consecutive to mast cell degranulation by allergen-specific IgE. Regulatory T cells (Treg) can control allergic sensitization and mast cell degranulation, yet their clinical benefit on anaphylactic symptoms is poorly documented. Here we investigated whether Treg action during the effector arm of the allergic response alleviates anaphylaxis.


METHODS
We used a validated model of IgE-mediated passive systemic anaphylaxis, induced by intravenous challenge with DNP-HSA in mice passively sensitized with DNP-specific IgE. Anaphylaxis was monitored by the drop in body temperature as well as plasma histamine and serum mMCP1 levels. The role of Treg was analyzed using MHC class II-deficient (Aβ(°/°)) mice, treatment with anti-CD25 or anti-CD4 mAbs and conditional ablation of Foxp3(+) Treg in DEREG mice. Therapeutic efficacy of Treg was also evaluated by transfer experiments using FoxP3-eGFP knock-in mice.


RESULTS
Anaphylaxis did not occur in mast cell-deficient W/W(v) mutant mice and was only moderate and transient in mice deficient for histamine receptor-1. Defects in constitutive Treg, either genetic or induced by antibody or toxin treatment resulted in a more severe and/or sustained hypothermia, associated with a rise in serum mMCP1, but not histamine. Adoptive transfer of Foxp3(+) Treg from either naïve or DNP-sensitized donors similarly alleviated body temperature loss in Treg-deficient DEREG mice.


CONCLUSIONS
Constitutive Foxp3(+) Treg can control the symptomatic phase of mast cell and IgE-dependent anaphylaxis in mice. This might open up new therapeutic avenues using constitutive rather than Ag-specific Treg for inducing tolerance in allergic patients.
CIRI, International Center for Infectiology Research, Mucosal immunity, Vaccination & Biotherapies Team, Université de Lyon, Lyon, France.
Reem
R
Kanjarawi
Michel
M
Dy
Emilie
E
Bardel
Tim
T
Sparwasser
Bertrand
B
Dubois
Salah
S
Mecheri
Dominique
D
Kaiserlian
D019264:Adoptive Transfer; D000707:Anaphylaxis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D004140:Dinitrophenols / Q000276:immunology; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006632:Histamine / Q000378:metabolism; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008407:Mast Cells / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D012709:Serum Albumin / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D004140:Dinitrophenols; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D000949:Histocompatibility Antigens Class II; D053645:Interleukin-2 Receptor alpha Subunit; D012709:Serum Albumin; C058064:dinitrophenyl-human serum albumin conjugate; D006632:Histamine