The Conduit System Transports Soluble Antigens from the Afferent Lymph to Resident Dendritic Cells in the T Cell Area of the Lymph Node

Michael Sixt, Nobuo Kanazawa, Manuel Selg, Thomas Samson, Gunnel Roos, Dieter P. Reinhardt, Reinhard Pabst, Manfred B. Lutz, Lydia Sorokin
2005 Immunity  
can phagocytose antigens and, subsequently, traffic via 22185 Lund the afferent lymphatics into the T cell area of the draining Sweden lymph node to initiate immune responses (Cavanagh 2 Department of Dermatology and Von Andrian, 2002; Manickasingham and Reis e University of Erlangen Sousa, 2001; Randolph, 2001). This pathway is well char-91052 Erlangen acterized, and there is recent evidence that steady state Germany migration of DC into the lymph node also occurs in 3 Department of
more » ... l Medicine I the healthy organism, which may serve to continuously University of Erlangen tolerize T cells against self antigens (Lutz and Schuler, 91054 Erlangen 2002; Steinman et al., 2003). A second pathway of anti-Germany gen delivery is less well defined and functions indepen-4 Department of Anatomy and Cell Biology dently of cellular trafficking along the lymphatics. Sev-McGill University eral studies have shown that peripherally applied Montreal H3A 2B2 soluble antigen is taken up, presented, and cross pre-Canada sented by resident DC in the T cell area of the draining 5 Department of Functional and Applied Anatomy lymph node. This happens before there is any detectable Medical School of Hannover immigration of DC from the periphery (Ingulli et al., 2002; 30625 Hannover Itano et al., 2003; Maurer et al., 2002; Pior et al., 1999). Germany These pathways of antigen delivery result in two temporally distinct "waves" of antigen presentation within the lymph node, which have been shown to induce function-Summary ally different T cell responses (Itano and Jenkins, 2003). However, to date, the physical means of transport of Resident dendritic cells (DC) within the T cell area of the soluble antigen from the injection site to the DC has the lymph node take up soluble antigens that enter not been identified, although it was speculated as early via the afferent lymphatics before antigen carrying DC as 1964 that the reticular fiber network of the lymph arrive from the periphery. The reticular network within node may play a central role in this process (Moe, 1964). the lymph node is a conduit system forming the infra- The reticular network is a three-dimensional frame of structure for the fast delivery of soluble substances collagen fibers that is closely ensheathed by the nonhefrom the afferent lymph to the lumen of high endothematopoietic, fibroblastic reticular cells (FRC), resulting lial venules (HEVs). Using high-resolution light microsin a scaffold that physically connects the subcapsular copy and 3D reconstruction, we show here that these and paracortical sinuses with the walls of the blood conduits are unique basement membrane-like struc- vessels (Anderson and Anderson, 1975; Anderson and tures ensheathed by fibroblastic reticular cells with Shaw, 1993; Gretz et al., 1997; Sainte-Marie and Peng, occasional resident DC embedded within this cell 1986; Ushiki et al., 1995). The FRC are tightly interconlayer. Conduit-associated DC are capable of taking up nected, resulting in a compartment that is separate from and processing soluble antigens transported within the T and B cell microenvironments. The concept that the conduits, whereas immigrated mature DC occur this network can serve as a conduit system for the transremote from the reticular fibers. The conduit system port of fluid and soluble substances within the lymph is, therefore, not a closed compartment that shuttles node stems from early morphological studies (Anderson substances through the lymph node but represents and Anderson, 1975; Sainte-Marie and Peng, 1986). In the morphological equivalent to the filtering function addition, recent studies by Shaw and coworkers (Gretz of the lymph node. et al., 2000) have shown that the conduit system allows low molecular weight substances (below 70 kDa), car-Introduction ried within the afferent lymph, to move directly from the subcapsular sinus to the lumen of HEVs without Most primary adaptive immune responses are initiated percolating through the lymphocyte compartment. in the T cell area of the lymph node. At this site, naive The physiological significance of this conduit system T cells, recirculating from the blood via HEVs, encounter was recently shown in two studies (Baekkevold et al., DC that present processed peptides of previously ac-2001; Palframan et al., 2001): the authors demonstrated quired antigens in an MHC context (Banchereau and that within minutes after subcutaneous injection, che-Steinman, 1998). Despite enormous progress in the field mokines are presented on the lumen of HEVs where of DC biology and rapidly accumulating data on molecuthey can act to recruit leukocytes. The fast delivery of chemokines occurred via the conduit system and was interpreted as a "remote control" function that serves *Correspondence: sixt@biochem.mpg.de Immunity 20
doi:10.1016/j.immuni.2004.11.013 pmid:15664156 fatcat:f5ctknb3rvh6dbnbvehliplu54