RESUMO
Activator of G-protein signaling 3 (AGS3, gene name G-protein signaling modulator-1, Gpsm1), an accessory protein for G-protein signaling, has functional roles in the kidney and CNS. Here we show that AGS3 is expressed in spleen, thymus, and bone marrow-derived dendritic cells, and is up-regulated upon leukocyte activation. We explored the role of AGS3 in immune cell function by characterizing chemokine receptor signaling in leukocytes from mice lacking AGS3. No obvious differences in lymphocyte subsets were observed. Interestingly, however, AGS3-null B and T lymphocytes and bone marrow-derived dendritic cells exhibited significant chemotactic defects as well as reductions in chemokine-stimulated calcium mobilization and altered ERK and Akt activation. These studies indicate a role for AGS3 in the regulation of G-protein signaling in the immune system, providing unexpected venues for the potential development of therapeutic agents that modulate immune function by targeting these regulatory mechanisms.
Assuntos
Proteínas de Transporte/metabolismo , Quimiocinas/metabolismo , Leucócitos/metabolismo , Transdução de Sinais , Motivos de Aminoácidos , Animais , Linfócitos B/citologia , Células da Medula Óssea/citologia , Cálcio/metabolismo , Quimiotaxia , Células Dendríticas/citologia , Feminino , Proteínas de Ligação ao GTP/metabolismo , Inibidores de Dissociação do Nucleotídeo Guanina , Sistema Imunitário , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Baço/citologia , Linfócitos T/citologia , Timócitos/citologiaRESUMO
Terminal deoxynucleotidyl transferase (TdT) places non-template-coded nucleotides (N additions) in the VH CDR3 of T cell receptors and immunoglobulins. Amino acids coded for by N additions are important in autoantibody binding of dsDNA in lupus. We hypothesized that a genetic lack of TdT would modulate disease in lupus-prone mice. To test this hypothesis, we derived TdT-deficient MRL/lpr mice. Serum levels of anti-dsDNA antibodies and anti-dsDNA producing splenocytes were significantly lower in the TdT(-) versus TdT(+) littermates. Albuminuria, glomerular IgG deposition, and pathologic renal disease were significantly reduced in the TdT(-) mice. Sequence analysis of anti-dsDNA hybridomas derived from TdT(-) mice revealed a lack of N additions, short VH CDR3 segments, yet the presence of VH CDR3 arginines. Thus, the genetic absence of TdT reduces autoantibody production and clinical disease in MRL/lpr mice, confirming the importance of N additions in the autoimmune response in these mice.
