IL-7–producing stromal cells are critical for lymph node remodeling

Abstract

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 ...

Defective Stromal Remodeling and Neutrophil Extracellular Traps in Lymphoid Tissues Favor the Transition from Autoimmunity to Lymphoma

“…We identifi ed stromal ECM modifi cations as a potential common denominator for this event and focused on the matricellular protein SPARC as a key regulator of relevant stromal changes. The end targets of ECM regulation in SLO are the lymphoid populations, as stromal cells support the survival of different subsets of T and B cells, providing prototypical homeostatic factors and functioning as antigen-presenting cells ( 47 ). During immune responses, SLO undergo profound architectural changes that are driven by stromal cells and involve the synthesis of ECM molecules, including matricellular proteins and collagens, which are somewhat unexpectedly implicated in the response outcome.…”

T cell and reticular network co-dependence in HIV infection

“…The two conditions, (15) and continuity of C(x) at x = X, allow us to find the two unknowns,x and c 0 . In Figure 8, we compare the steady-state values of the mean number of cells,n, and the mean IL-7 level,x, obtained from numerical solution of the heterogeneous population model introduced in Section 3, with the following approximation, obtained using only the first term in (15) and (16) …”

“…The T-cell zones of lymph nodes (LN), where the encounters between T cells and antigen-presenting cells that initiate immune responses occur [9,10], is also the site where T-cells access the IL-7 resource they need to survive in the absence of infection. One subset of lymph node stromal cells, the fibroblastic reticular cells in the T-cell zone, produce IL-7 [11][12][13][14][15][16]. Within a T-cell population, IL-7 receptor expression varies from cell to cell; those with higher expression are believed to be more likely to divide [17,18].…”

Innate Immune Cell CD45 Regulates Lymphopenia-Induced T Cell Proliferation

“…The stromal cells responsible for IL-7 production in secondary lymphoid organs are mainly fibroblastic reticular cells (FRCs) and lymphatic endothelial cells (36), which can both be identified as CD45 2 gp38 + cells (37). Because we were unable to use CD45 as a marker for stromal cell discrimination, we developed a lineage mix (CD11b, CD11c, NK1.1, CD4, and CD8) that labeled virtually all of the CD45 + cells in the lymph nodes of RAGKO mice.…”