RESUMO
The formation of lymph nodes is a complex process crucially controlled through triggering of LTbetaR on mesenchymal cells by LTalpha(1)beta(2) expressing lymphoid tissue inducer (LTi) cells. This leads to the induction of chemokines to attract more hematopoietic cells and adhesion molecules to retain them. In this study, we show that the extravasation of the first hematopoietic cells at future lymph node locations occurs independently of LTalpha and that these cells, expressing TNF-related activation-induced cytokine (TRANCE), are the earliest LTi cells. By paracrine signaling the first expression of LTalpha(1)beta(2) is induced. Subsequent LTbetaR triggering on mesenchymal cells leads to their differentiation to stromal organizers, which now also start to express TRANCE, IL-7, as well as VEGF-C, in addition to the induced adhesion molecules and chemokines. Both TRANCE and IL-7 will further induce the expression of LTalpha(1)beta(2) on newly arrived immature LTi cells, resulting in more LTbetaR triggering, generating a positive feedback loop. Thus, LTbetaR triggering by LTi cells during lymph node development creates a local environment to which hematopoietic precursors are attracted and where they locally differentiate into fully mature, LTalpha(1)beta(2) expressing, LTi cells. Furthermore, the same signals may regulate lymphangiogenesis to the lymph node through induction of VEGF-C.
Assuntos
Proteínas Angiogênicas/biossíntese , Citocinas/biossíntese , Linfonodos/imunologia , Receptor beta de Linfotoxina/fisiologia , Transdução de Sinais/imunologia , Regulação para Cima/imunologia , Proteínas Angiogênicas/genética , Animais , Diferenciação Celular/imunologia , Movimento Celular/imunologia , Células Cultivadas , Citocinas/genética , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Linfonodos/citologia , Linfonodos/embriologia , Linfonodos/metabolismo , Tecido Linfoide/embriologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Heterotrímero de Linfotoxina alfa1 e beta2/biossíntese , Heterotrímero de Linfotoxina alfa1 e beta2/deficiência , Heterotrímero de Linfotoxina alfa1 e beta2/genética , Heterotrímero de Linfotoxina alfa1 e beta2/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ligante RANK/biossíntese , Ligante RANK/genética , Células Estromais/imunologia , Células Estromais/metabolismoRESUMO
Toll-like receptor (TLR)-dependent pathways control the production of IFNalphabeta, a key cytokine in innate immune control of viruses including mouse cytomegalovirus (MCMV). The lymphotoxin (LT) alphabeta-LTbeta receptor signaling pathway is also critical for defense against MCMV and thought to aid in the IFNbeta response. We find that upon MCMV infection, mice deficient for lymphotoxin (LT)alphabeta signaling cannot mount the initial part of a biphasic IFNalphabeta response, but show normal levels of IFNalphabeta during the sustained phase of infection. Significantly, the LTalphabeta-dependent, IFNalphabeta response is independent of TLR signaling. B, but not T, cells expressing LTbeta are essential for promoting the initial IFNalphabeta response. LTbetaR expression is required strictly in splenic stromal cells for initial IFNalphabeta production to MCMV and is dependent upon the NF-kappaB-inducing kinase (NIK). These results reveal a TLR-independent innate host defense strategy directed by B cells in communication with stromal cells via the LTalphabeta cytokine system.