RESUMEN
While studying the plasma cell (PC) compartment in human tonsils, we identified that immunoglobulin kappa or lambda chain-expressing PCs are the main cells expressing granzyme B (GrzB). In vitro studies revealed that activated B cells differentiated into GrzB-expressing PCs when co-cultured with macrophages and follicular helper T cells. This effect could be reproduced on combined stimulation of IL-15 (produced by macrophages) and IL-21 (produced by T follicular helper cells) in a STAT3-dependent manner. Whereas IL-21 triggers the transcription of mRNA of GrzB, IL-15 synergizes the translation of GrzB proteins. The precise role of GrzB in PC biology remains to be understood and studies in mice will not help as their PCs do not express GrzB.
Asunto(s)
Granzimas/metabolismo , Interleucina-15/inmunología , Interleucinas/inmunología , Macrófagos/inmunología , Células Plasmáticas/enzimología , Linfocitos T Colaboradores-Inductores/inmunología , Diferenciación Celular , Células Cultivadas , Técnicas de Cocultivo , Regulación de la Expresión Génica , Granzimas/genética , Humanos , Cadenas kappa de Inmunoglobulina/metabolismo , Cadenas lambda de Inmunoglobulina/metabolismo , Activación de Linfocitos , Tonsila Palatina/citología , Factor de Transcripción STAT3/metabolismo , Activación TranscripcionalRESUMEN
In tonsils, CD138(+) plasma cells (PCs) are surrounded by CD163(+) resident macrophages (Ms). We show here that human Ms (isolated from tonsils or generated from monocytes in vitro) drive activated B cells to differentiate into CD138(+)CD38(++) PCs through secreted CXCL10/IP-10 and VCAM-1 contact. IP-10 production by Ms is induced by B cell-derived IL-6 and depends on STAT3 phosphorylation. Furthermore, IP-10 amplifies the production of IL-6 by B cells, which sustains the STAT3 signals that lead to PC differentiation. IP-10-deficient mice challenged with NP-Ficoll show a decreased frequency of NP-specific PCs and lower titers of antibodies. Thus, our results reveal a novel dialog between Ms and B cells, in which IP-10 acts as a PC differentiation factor.