The stromal scaffold of the lymph node (LN) paracortex is built by fibroblastic reticular cells (FRCs). Conditional ablation of lymphotoxin-β receptor (LTβR) expression in LN FRCs and their mesenchymal progenitors in developing LNs revealed that LTβR-signaling in these cells was not essential for the formation of LNs. Although T cell zone reticular cells had lost podoplanin expression, they still formed a functional conduit system and showed enhanced expression of myofibroblastic markers. However, essential immune functions of FRCs, including homeostatic chemokine and interleukin-7 expression, were impaired. These changes in T cell zone reticular cell function were associated with increased susceptibility to viral infection. Thus, myofibroblasic FRC precursors are able to generate the basic T cell zone infrastructure, whereas LTβR-dependent maturation of FRCs guarantees full immunocompetence and hence optimal LN function during infection.

Nonhematopoietic stromal cells of secondary lymphoid organs form important scaffold and fluid transport structures, such as lymph node (LN) trabeculae, lymph vessels, and conduits. Furthermore, through the production of chemokines and cytokines, these cells generate a particular microenvironment that determines lymphocyte positioning and supports lymphocyte homeostasis. IL-7 is an important stromal cell-derived cytokine that has been considered to be derived mainly from T-cell zone fibroblastic reticular cells. We show here that lymphatic endothelial cells ( IntroductionIL-7 is an important cytokine that controls development and activation of different immune cells. 1 The broad expression of this cytokine in primary and secondary lymphoid organs is indicative for its multiple functions. In bone marrow, IL-7 acts on the development of B cells by determining B-cell lineage commitment 2 and regulating immunoglobulin gene arrangement. 3,4 In the thymus, IL-7 serves as a key factor for thymocyte survival and maturation. 5,6 Likewise, IL-7 provides antiapoptotic and proliferative signals to T cells within secondary lymphoid organs and is hence critical for peripheral T-cell homeostasis. 7,8 Furthermore, some intrinsic functions of marginal zone B cells and structural organization of the splenic marginal zone microenvironment depend, at least partially, on IL-7. 9 Besides these effects on T and B lymphocytes, IL-7 can impact on the development of dendritic cells 10 and NK T cells. 11 Hence, because of its pleiotropic functions, IL-7 can be regarded as one of the central regulators of immune cell homeostasis.Besides its direct impact on immune cells, IL-7 acts also on the formation of secondary lymphoid organs. During lymph node (LN) development, for example, IL-7 is produced by VCAM1 ϩ ICAM1 ϩ mesenchymal cells, also known as stromal organizer cells. 12 Stromal cell-derived IL-7 promotes survival of lymphoid tissue inducer (LTi) cells 13 that initiate lymphotoxin-␤ receptor-dependent formation of the LN environment. 14 The importance of IL-7 in LN development and maturation is illustrated by the absence of most peripheral LNs in IL-7R␣-deficient mice. 15,16 Furthermore, overexpression of IL-7 results in the formation of ectopic lymphoid tissues, 17 suggesting that IL-7 critically contributes to the adaptation of lymphoid organ structure during immune reactions.IL-7 production is tightly regulated and detection of both IL-7 protein and mRNA in situ requires highly sensitive detection systems. 18 It has been suggested that IL-7 produced by stromal cells in secondary lymphoid organs is locally consumed by IL-7R␣-expressing cells and that a production-consumption equilibrium regulates lymphocyte homeostasis. 19 Indeed, a recent study suggested that T-cell homeostasis is controlled by T-cell zone fibroblastic reticular cells (FRCs), which exhibited higher IL-7 expression compared with bulk endothelial cell preparations. 20 However, not all IL-7R␣-expressing cells reside in the T-cell zone. For example, IL-7R␣ ϩ ␥␦ T cells ...

Alloimmune T cell responses induce graft-versus-host disease (GVHD), a serious complication of allogeneic bone marrow transplantation (allo-BMT). Although Notch signaling mediated by Delta-like 1/4 (DLL1/4) Notch ligands has emerged as a major regulator of GVHD pathogenesis, little is known about the timing of essential Notch signals and the cellular source of Notch ligands after allo-BMT. Here, we have shown that critical DLL1/4-mediated Notch signals are delivered to donor T cells during a short 48-hour window after transplantation in a mouse allo-BMT model. Stromal, but not hematopoietic, cells were the essential source of Notch ligands during in vivo priming of alloreactive T cells. GVHD could be prevented by selective inactivation of Dll1 and Dll4 in subsets of fibroblastic stromal cells that were derived from chemokine Ccl19-expressing host cells, including fibroblastic reticular cells and follicular dendritic cells. However, neither T cell recruitment into secondary lymphoid organs nor initial T cell activation was affected by Dll1/4 loss. Thus, we have uncovered a pathogenic function for fibroblastic stromal cells in alloimmune reactivity that can be dissociated from their homeostatic functions. Our results reveal what we believe to be a previously unrecognized Notch-mediated immunopathogenic role for stromal cell niches in secondary lymphoid organs after allo-BMT and define a framework of early cellular and molecular interactions that regulate T cell alloimmunity.

Endothelial cell ablation of the lymphotoxin-β receptor results in failure to develop peripheral lymph nodes and normal high endothelial venues, which impairs lymphocyte homing.

Fasnacht et al. now show that fibroblasts in secondary lymphoid organs are responsible for the production of Notch ligands regulating the differentiation of immune cells

Fibroblastic reticular cells (FRCs) of secondary lymphoid organs form distinct niches for interaction with hematopoietic cells. We found here that production of the cytokine IL-15 by FRCs was essential for the maintenance of group 1 innate lymphoid cells (ILCs) in Peyer's patches and mesenteric lymph nodes. Moreover, FRC-specific ablation of the innate immunological sensing adaptor MyD88 unleashed IL-15 production by FRCs during infection with an enteropathogenic virus, which led to hyperactivation of group 1 ILCs and substantially altered the differentiation of helper T cells. Accelerated clearance of virus by group 1 ILCs precipitated severe intestinal inflammatory disease with commensal dysbiosis, loss of intestinal barrier function and diminished resistance to colonization. In sum, FRCs act as an 'on-demand' immunological 'rheostat' by restraining activation of group 1 ILCs and thereby preventing immunopathological damage in the intestine.

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Background:We studied ribosome and nucleoid distribution in Escherichia coli under growth and quiescence. Results: Spatially segregated ribosomes and nucleoids show drastically altered distribution in stationary phase or when treated with drugs affecting translation, transcription, nucleoid-topology, or cytoskeleton. Ribosome inheritance in daughter cells is frequently unequal. Conclusion: Cellular growth processes modulate ribosome and nucleoid distribution. Significance: This provides insight into subcellular organization of molecular machines.