Interleukin 7 is essential for the survival of naive T lymphocytes. Despite its importance, its cellular source in the periphery remains poorly defined. Here we report a critical function for lymph node access in T cell homeostasis and identify T zone fibroblastic reticular cells in these organs as the main source of interleukin 7. In vitro, T zone fibroblastic reticular cells were able to prevent the death of naive T lymphocytes but not of B lymphocytes by secreting interleukin 7 and the CCR7 ligand CCL19. Using gene-targeted mice, we demonstrate a nonredundant function for CCL19 in T cell homeostasis. Our data suggest that lymph nodes and T zone fibroblastic reticular cells have a key function in naive CD4(+) and CD8(+) T cell homeostasis by providing a limited reservoir of survival factors.

Adaptive immunity is initiated in T-cell zones of secondary lymphoid organs. These zones are organized in a rigid 3D network of fibroblastic reticular cells (FRCs) that are a rich cytokine source. In response to lymph-borne antigens, draining lymph nodes (LNs) expand several folds in size, but the fate and role of the FRC network during immune response is not fully understood. Here we show that T-cell responses are accompanied by the rapid activation and growth of FRCs, leading to an expanded but similarly organized network of T-zone FRCs that maintains its vital function for lymphocyte trafficking and survival. In addition, new FRC-rich environments were observed in the expanded medullary cords. FRCs are activated within hours after the onset of inflammation in the periphery. Surprisingly, FRC expansion depends mainly on trapping of naïve lymphocytes that is induced by both migratory and resident dendritic cells. Inflammatory signals are not required as homeostatic T-cell proliferation was sufficient to trigger FRC expansion. Activated lymphocytes are also dispensable for this process, but can enhance the later growth phase. Thus, this study documents the surprising plasticity as well as the complex regulation of FRC networks allowing the rapid LN hyperplasia that is critical for mounting efficient adaptive immunity.lymph node swelling | fibroblasts | stromal cells | lymphotoxin | MyD88

Aging is associated with a gradual loss of naïve T cells and a reciprocal increase in the proportion of memory T cells. While reduced thymic output is important, age-dependent changes in factors supporting naïve T cells homeostasis may also be involved. Indeed, we noted a dramatic decrease in the ability of aged mice to support survival and homeostatic proliferation of naïve T cells. The defect was not due to a reduction in IL-7 expression, but from a combination of changes in the secondary lymphoid environment that impaired naïve T cell entry and access to key survival factors. We observed an age-related shift in the expression of homing chemokines and structural deterioration of the stromal network in T cell zones. Treatment with IL-7/mAb complexes can restore naïve T cell homeostatic proliferation in aged mice. Our data suggests that homeostatic mechanisms that support the naïve T cell pool deteriorate with age.

Antibody-secreting plasma cells (PCs) arise rapidly during adaptive immunity to control infections. The early PCs are retained within the reactive lymphoid organ where their localization and homeostasis rely on extrinsic factors, presumably produced by local niche cells. While myeloid cells have been proposed to form those niches, the contribution by colocalizing stromal cells has remained unclear. Here, we characterized a subset of fibroblastic reticular cells (FRCs) that forms a dense meshwork throughout medullary cords of lymph nodes (LNs) where PCs reside. This medullary FRC type is shown to be anatomically, phenotypically, and functionally distinct from T zone FRCs, both in mice and humans. By using static and dynamic imaging approaches, we provide evidence that medullary FRCs are the main cell type in contact with PCs guiding them in their migration. Medullary FRCs also represent a major local source of the PC survival factors IL-6, BAFF, and CXCL12, besides also producing APRIL. In vitro, medullary FRCs alone or in combination with macrophages promote PC survival while other LN cell types do not have this property. Thus, we propose that this FRC subset, together with medullary macrophages, forms PC survival niches within the LN medulla, and thereby helps in promoting the rapid development of humoral immunity, which is critical in limiting early pathogen spread.

Interleukin-7 (IL-7 IntroductionDendritic cells (DCs) are antigen-presenting cells that are critical for inducing immunity as well as tolerance of T cells. Based on phenotype, localization, and function, several CD11c ϩ DC subsets can be identified in murine secondary lymphoid organs (SLOs). 1,2 Conventional DCs (cDCs) are resident within SLOs, have an immature phenotype (MHCIIint ), and sample antigens locally. They can be divided into CD8␣ ϩ and CD8␣ Ϫ subpopulations that differ in immune function, cytokine expression, and antigen presentation. In contrast, plasmacytoid DCs (pDCs; MHCII low ) are poor antigen-presenting cells and produce type I interferon after stimulation by viral or bacterial infection. In skin-draining lymph nodes (LNs), a third DC type often referred to as migratory DCs (migDCs; MHCII hi ) is found. These comprise dermal DCs and epidermal Langerhans cells, which capture antigens in the skin and migrate via the lymphatics to the draining LN to activate antigen-specific T cells. 1,2 The capacity of DCs to present self as well as foreign antigens in SLOs is limited due to their rapid turnover. Under steady-state conditions, cDCs in spleen and LN are almost completely replaced within 3 to 5 days, while pDCs in spleen and migDCs in LN have an approximate half-life of 10 and 20 days, respectively. [3][4][5] Only a few factors regulating the maintenance of lymphoid tissue DCs in vivo are known, including lymphotoxin ␤-receptor (LT␤R) and bcl-x L . 6,7 However, the short lifespan of cDCs in resting SLOs suggests that they are continuously replaced by precursor cells immigrating into the tissue. Some of the replacement may also occur locally as indicated by the presence of proliferating DC precursors. 6,[8][9][10] The precursors of most DCs are thought to reside in the bone marrow (BM) and share early progenitors with other hematopoietic cell lineages. Hematopoietic stem cells (HSCs) decide first between a lymphoid versus myeloid cell fate by differentiating into either common lymphoid progenitors (CLPs) or common myeloid progenitors (CMPs). 1,2 CLPs can give rise to natural killer (NK), T, and B cells, while CMPs can become macrophages, granulocytes, erythrocytes, and megakaryocytes. In addition, both CLPs and CMPs have the potential to give rise to cDCs and pDCs in mice and men, suggesting considerable plasticity in DC development. 1,2,[11][12][13] However, the relative contributions of CLPs and CMPs to the peripheral DC pool is only partially understood.Over the past few years, several cytokines and transcription factors regulating DC development have been identified. The cytokine FMSlike tyrosine kinase 3 ligand (Flt3L), which binds to its receptor Flt3 and signals via the transcription factor signal transducers and activators of transcription (STAT) 3, is important for DC development in vitro and in vivo. 14-17 Interestingly, adult Flt3L-and STAT3-deficient mice still develop 10% to 65% of splenic cDCs and pDCs, indicating the involvement of other factors. 14-16 A good candidate is STAT5, as m...