RESUMEN
Emerging evidence indicates that innate immunodeficiency syndromes are linked to mutations in innate receptors and to specific infections. X-linked lymphoproliferative syndrome type-2 (XLP-2) is associated with deficiency in X-linked inhibitor of apoptosis protein (XIAP), with poorly understood molecular mechanisms. Here we showed that XIAP deficiency selectively impaired B-cell chronic lymphocytic leukemia/lymphoma 10 (BCL10)-mediated innate responses to dectin-1 ligands but did not affect responses to various Toll-like receptor agonists. Consequently, Xiap(-/-) mice became highly vulnerable on Candida albicans infection. The compromised early innate responses led to the persistent presence of C albicans and inflammatory cytokines in Xiap(-/-) mice. Furthermore, priming of Xiap(-/-) mice with the dectin-1 ligand curdlan alone resulted in XLP-2-like syndromes. Restoration of dectin-1-induced Rac1 activation and phagocytosis by resolvin D1, but not up-regulation of nuclear factor-κB, rescued Xiap(-/-) mice from C albicans lethal infection. Therefore, development of XLP-2 in XIAP-deficient patients could be partly due to sustained inflammation as a consequence of defective BCL10-dependent innate immunity toward specific pathogens. Importantly, our results suggest the potential therapeutic value of resolvin D1 in the treatment of XLP-2 and innate immunodeficiency syndromes.
Asunto(s)
Candidiasis/inmunología , Candidiasis/patología , Inmunidad Innata , Proteínas Inhibidoras de la Apoptosis/deficiencia , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proteína 10 de la LLC-Linfoma de Células B , Candida albicans/efectos de los fármacos , Candida albicans/fisiología , Candidiasis/microbiología , Receptores ErbB/metabolismo , Enfermedades Genéticas Ligadas al Cromosoma X/inmunología , Enfermedades Genéticas Ligadas al Cromosoma X/patología , Humanos , Imidazoles/farmacología , Inmunidad Innata/efectos de los fármacos , Proteínas Inhibidoras de la Apoptosis/metabolismo , Lectinas Tipo C/agonistas , Lectinas Tipo C/metabolismo , Lipopéptidos/farmacología , Lipopolisacáridos/farmacología , Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/patología , Lisina/metabolismo , Lisofosfolípidos/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , FN-kappa B/metabolismo , Fagocitosis/efectos de los fármacos , Poli I-C/farmacología , Unión Proteica/efectos de los fármacos , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores Toll-Like/metabolismo , Factor de Necrosis Tumoral alfa/farmacología , Ubiquitinación/efectos de los fármacos , beta-GlucanosRESUMEN
Paxillin is an adaptor protein associated with focal adhesion complex, and is activated by tyrosine phosphorylation through focal adhesion kinase (FAK) and Src kinase. Recent studies reveal that serine phosphorylation of paxillin by JNK and p38 MAPK is essential for cell migration or neurite extension, but their cellular targets remain unclear. In this study, we examined the requirement of paxillin phosphorylation by p38 MAPK or JNK in T-cell motility and activation using paxillin mutants at the respective phosphorylation sites, Ser85, and Ser178. (S85A)-paxillin, (S178A)-paxillin, or (S85A/S178A)-paxillin inhibited the motility of NIH/3T3 fibroblasts, but did not interfere with T-cell migration and integrin-mediated T-cell adhesion. In contrast, activation of T cells was effectively suppressed by (S85A/S178A)-paxillin. Transgenic (S85A/S178A)-paxillin expression inhibited T-cell proliferation and reduced the production of IL-2, IFN-γ, and IL-4. In searching for signals modulated by (S85A/S178A)-paxillin, we found that NFAT activation was specifically blocked by (S85A/S178A)-paxillin. This could be partly attributed to diminished stromal interaction molecule 1 (STIM1) expression and attenuated TCR-induced Ca(2+) influx. Our results demonstrate that dual phosphorylation of paxillin by JNK and p38 MAPK is essential for T-cell activation and suggest that NFAT is a functional target of the JNK/p38 phosphorylated paxillin.