title: CARMA1 is necessary for optimal T cell responses in a murine model of allergic asthma.
abstract: CARMA1 is a lymphocyte-specific scaffold protein necessary for T cell activation. Deletion of CARMA1 prevents the development of allergic airway inflammation in a mouse model of asthma due to a defect in naive T cell activation. However, it is unknown if CARMA1 is important for effector and memory T cell responses after the initial establishment of inflammation, findings that would be more relevant to asthma therapies targeted to CARMA1. In the current study, we sought to elucidate the role of CARMA1 in T cells that have been previously activated. Using mice in which floxed CARMA1 exons can be selectively deleted in T cells by OX40-driven Cre recombinase (OX40(+/Cre)CARMA1(F/F)), we report that CD4(+) T cells from these mice have impaired T cell reactivation responses and NF-κB signaling in vitro. Furthermore, in an in vivo recall model of allergic airway inflammation that is dependent on memory T cell function, OX40(+/Cre)CARMA1(F/F) mice have attenuated eosinophilic airway inflammation, T cell activation, and Th2 cytokine production. Using MHC class II tetramers, we demonstrate that the development and maintenance of Ag-specific memory T cells is not affected in OX40(+/Cre)CARMA1(F/F) mice. In addition, adoptive transfer of Th2-polarized OX40(+/Cre)CARMA1(F/F) Ag-specific CD4(+) T cells into wild-type mice induces markedly less airway inflammation in response to Ag challenge than transfer of wild-type Th2 cells. These data demonstrate a novel role for CARMA1 in effector and memory T cell responses and suggest that therapeutic strategies targeting CARMA1 could help treat chronic inflammatory disorders such as asthma.
authors.affiliation: Pulmonary and Critical Care Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Ravisankar A
authors.initials: RA
authors.lastname: Ramadas
authors.forename: Marly I
authors.initials: MI
authors.lastname: Roche
authors.forename: James J
authors.initials: JJ
authors.lastname: Moon
authors.forename: Thomas
authors.initials: T
authors.lastname: Ludwig
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Medoff
mesh_terms: D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D053468:CARD Signaling Adaptor Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016764:Cell Polarity / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000502:physiology; D019426:Integrases / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000502:physiology; D053262:Receptors, OX40 / Q000096:biosynthesis / Q000235:genetics; D012130:Respiratory Hypersensitivity / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000637:transplantation
chemical_list: D053468:CARD Signaling Adaptor Proteins; C496467:Card11 protein, mouse; D018836:Inflammation Mediators; D011948:Receptors, Antigen, T-Cell; D053262:Receptors, OX40; C505716:TNFRSF4 protein, human; C045073:Cre recombinase; D019426:Integrases
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