CD4+CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40-OX40L interaction.
T regulatory (Treg) cells play a role in the suppression of immune responses, thus serving to induce tolerance and control autoimmunity. Here, we explored whether Treg cells influence the immediate hypersensitivity response of mast cells (MCs). Treg cells directly inhibited the FcvarepsilonRI-dependent MC degranulation through cell-cell contact involving OX40-OX40L interactions between Treg cells and MCs, respectively. When activated in the presence of Treg cells, MCs showed increased cyclic adenosine monophosphate (cAMP) concentrations and reduced Ca(2+) influx, independently of phospholipase C (PLC)-gamma2 or Ca(2+) release from intracellular stores. Antagonism of cAMP in MCs reversed the inhibitory effects of Treg cells, restoring normal Ca(2+) responses and degranulation. Importantly, the in vivo depletion or inactivation of Treg cells caused enhancement of the anaphylactic response. The demonstrated crosstalk between Treg cells and MCs defines a previously unrecognized mechanism controlling MC degranulation. Loss of this interaction may contribute to the severity of allergic responses.
Gri
Giorgia
G
Department of Biomedical Science and Technology, University of Udine, 33100 Udine, Italy.
Piconese
Silvia
S
Frossi
Barbara
B
Manfroi
Vanessa
V
Merluzzi
Sonia
S
Tripodo
Claudio
C
Viola
Antonella
A
Odom
Sandra
S
Rivera
Juan
J
Colombo
Mario P
MP
Pucillo
Carlo E
CE
D000818:Animals; D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006636:Histamine Release; D006801:Humans; D006967:Hypersensitivity / Q000276:immunology / Q000378:metabolism; D008407:Mast Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053278:OX40 Ligand; D051966:Phospholipase C gamma / Q000378:metabolism*; D053262:Receptors, OX40 / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism*
D008562:Membrane Glycoproteins; D053278:OX40 Ligand; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse; C504586:Tnfsf4 protein, mouse; D048069:Tumor Necrosis Factors; D051966:Phospholipase C gamma; D002118:Calcium