IntroductionSeveral subsets of stromal cells, in particular follicular dendritic cells (FDCs) and fibroblastic reticular cells (FRCs), are found within secondary lymphoid organs where they play a key role in the initiation and maintenance of efficient immune responses. FDCs are restricted to germinal centers (GCs) and allow B-cell migration, selection, and differentiation through a complex set of survival factors including BCR-mediated signal, chemokines, cytokines, and adhesion molecules. 1 B-cell selection relies on an affinitybased competition for the fixation of antigen, presented as immune complexes by CD21 hi CD35 hi FDCs. Only B cells with high-affinity BCR receive survival signals from FDCs, capture antigen, and present it to CD4 ϩ T cells that deliver additional survival and maturation signals. 2,3 Conversely, FRCs are less well characterized. They are tightly interconnected in the paracortex of lymph nodes (LNs) where they secrete and ensheath various extracellular matrix components, thus building an intricate network of conduits, connecting afferent lymphatic vessels to high endothelial venules (HEVs). 4 This conduit system allows the rapid transport of soluble antigens from the periphery to the resident myeloid immature dendritic cells (DCs). 5 In addition, part of this reticular network called cortical ridge favors B, T, and DC recruitment and reciprocal interactions, in particular through the production of constitutive and inflammatory chemokines. 6,7 CCL19, CCL21, and CXCL12 are involved in the migration of mature myeloid DCs and naive B and T cells, whereas CXCL9, CXCL10, and CCL5 are crucial for the migration of activated T cells and plasmacytoid DCs. [8][9][10] Strikingly, CCL19 and CCL21 are not synthesized by human HEVs but rather by stromal cells in the T-cell zone. 11,12 These chemokines further reach luminal surface of HEVs by endothelial uptake and transcytosis. FRCs provide therefore a favorable and highly specialized lymphoid environment for immune cell migration and activation.The ontogeny of FRCs and FDCs remains unclear, but these cells are supposed to be of mesenchymal origin. LN organogenesis in the mouse relies on the interaction between CD45 Ϫ VCAM-1 ϩ ICAM-1 ϩ mesenchymal cells and CD45 ϩ CD4 ϩ CD3 Ϫ lymphoid tissue inducer cells in the LN anlagen. 13 A prominent role is attributed to lymphotoxin-␤ receptor (LT␤R) triggering by membrane-bound LT␣1␤2 (LT) and to tumor necrosis factor receptor 1 (TNFR1)/tumor necrosis factor-␣ (TNF). 14,15 Adult lymphoid tissues are highly dynamic structures that retain several features of embryonic organization. 16 Functional mouse FRCs able to construct a reticular meshwork and to secrete inflammatory chemokines could be generated in vitro by stimulation of LN-derived stromal cell lines using a combination of TNF and LT. 17 In vivo, transgenic expression of LT or injection of newborn LN-derived The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefo...

Accumulating evidence indicates that infiltrating stromal cells contribute directly and indirectly to tumor growth in a wide range of cancers. In follicular lymphoma (FL), malignant B cells are found admixed with heterogeneous lymphoid-like stro-mal cells within invaded lymph nodes and BM. In addition, mesenchymal stromal cells (MSCs) support in vitro FL B-cell survival, in particular after their engagement toward lymphoid differentiation. We show here that BM-MSCs obtained from patients with FL (FL-MSCs) display a specific gene expression profile compared with MSCs obtained from healthy age-matched donors (HD-MSCs). This FL-MSC signature is significantly enriched for genes associated with a lymphoid-like commitment. Interestingly, CCL2 could be detected at a high level within the FL-cell niche, is up-regulated in HD-MSCs by coculture with malignant B cells, and is overexpressed by FL-MSCs, in agreement with their capacity to recruit mono-cytes more efficiently than HD-MSCs. Moreover, FL-MSCs and macrophages cooperate to sustain malignant B-cell growth, whereas FL-MSCs drive monocyte differentiation toward a proangiogenic and lipopolysaccharide-unresponsive phenotype close to that of tumor-associated mac-rophages. Altogether, these results highlight the complex role of FL stromal cells that promote direct tumor B-cell growth and orchestrate FL-cell niche, thus emerging as a potential therapeutic target in this disease. (Blood. 2012;119(11):2556-2567)

Follicular lymphoma (FL) B cells contract tight connections with their microenvironment, which governs the pathogenesis and progression of the disease. Indeed, specific immune response gene signatures, obtained from whole biopsy samples, have been associated with patient survival. In this study, we performed gene expression profiling of purified B cell and non-B cell compartments obtained from FL and reactive lymph nodes. We identified 677 non-redundant genes defining the FL interface and involving 26 FL-specific functional networks. This approach highlighted an interleukin-4 (IL-4)-centered pathway associated with an activation of signal transducer and activator of transcription 6 (STAT6), which favors overexpression of IL-4-target genes. In addition, FL microenvironment was characterized by a strong enrichment in follicular helper T cells (T FH ), as demonstrated through transcriptomic and flow cytometry analyses. The majority of phospho-STAT6 pos B cells were located at the vicinity of cells expressing the programmed death 1 (PD-1) T FH marker. Moreover, purified FL-derived T FH , expressed IL4 at very high levels compared with purified tonsil-derived T FH or non-T FH microenvironment. Altogether, our study demonstrated that tumorinfiltrating T FH specifically express functional IL-4 in FL, creating an IL-4-dependent T FH -B cell axis. This cross talk could sustain FL pathogenesis and represent a new potential therapeutic target.