Little is known about the molecular mechanisms that determine the entry into the lymph node and intranodal positioning of lymph-derived cells. By injecting cells directly into afferent lymph vessels of popliteal lymph nodes, we demonstrate that lymph-derived T cells entered lymph-node parenchyma mainly from peripheral medullary sinuses, whereas dendritic cells (DCs) transmigrated through the floor of the subcapsular sinus on the afferent side. Transmigrating DCs induced local changes that allowed the concomitant entry of T cells at these sites. Signals mediated by the chemokine receptor CCR7 were absolutely required for the directional migration of both DCs and T cells into the T cell zone but were dispensable for the parenchymal entry of lymph-derived T cells and dendrite probing of DCs. Our findings provide insight into the molecular and structural requirements for the entry into lymph nodes and intranodal migration of lymph-derived cells of the immune system.

The requirements for BALT formation are pathogen-dependent and, in the absence of FDC maturation, IL-17 can drive BALT formation via CXCL12 B cell recruitment.

The continuous migration of immune cells between lymphoid and nonlymphoid organs is a key feature of the immune system, facilitating the distribution of effector cells within nearly all compartments of the body. Furthermore, reaching their correct position within primary, secondary, or tertiary lymphoid organs is a prerequisite to ensure immune cells' unimpaired differentiation, maturation, and selection, as well as their activation or functional silencing. The superfamilies of chemokines and chemokine receptors are of major importance in guiding immune cells to and within lymphoid and nonlymphoid tissues. In this review we focus on the role of the chemokine system in the migration dynamics of immune cells within lymphoid organs at the steady state and on how these dynamics are affected by infectious and inflammatory processes.

CCR7 is a homeostatically expressed chemokine receptor that is known to regulate the homing of various types of immune cells to primary, secondary, and tertiary lymphoid organs. Recent evidence suggests that, in addition to controlling cell migration, CCR7-mediated signals affect T-cell homeostasis in lymph nodes at various levels and also influence T-cell activation and polarization. In this review, we highlight these findings and discuss recently proposed functions of the CCR7 pathway in the induction and maintenance of chronic inflammation.

The chemokine receptor CXCR5 is primarily expressed on B cells and Tfh cells and facilitates their migration towards B cell follicles. In the present study we investigated the role of the CXCL13/CXCR5 axis in the pathogenesis of rheumatoid arthritis (RA) and specifically addressed the impact of CXCR5-mediated T and B cell migration in this disease. Employing collagen-induced arthritis (CIA) we identify CXCR5 as an absolutely essential factor for the induction of inflammatory autoimmune arthritis. Cxcr5-deficient mice and mice selectively lacking Cxcr5 on T cells were completely resistant to CIA, showed impaired germinal center responses and failed to mount an IgG1 antibody response to collagen II. Selective ablation of CXCR5 expression in B cells also led to suppression of CIA owing to diminished GC responses in secondary lymphoid organs (SLO) and impaired anti-collagen II antibody production. Chimeric mice harboring Cxcr5-proficient and Cxcr5-deficient immune cells revealed SLO and not the synovial tissue as the compartment where CXCR5-mediated cell migration induces autoimmune inflammation in arthritis. Thus our data demonstrate that CXCR5-mediated co-localization of Tfh cells and B cells in SLOs is absolutely essential for the induction of RA and identify CXCR5 and Tfh cells as promising therapeutic targets for the treatment of RA.

The chemokine receptor CCR7 and its ligands CCL19 and CCL21 guide the homing and positioning of dendritic and T cells in lymphoid organs, thereby contributing to several aspects of adaptive immunity and immune tolerance. In the present study, we investigated the role of CCR7 in the pathogenesis of collagen-induced arthritis (CIA). By using a novel anti-human CCR7 antibody and humanized CCR7 mice, we evaluated CCR7 as a target in this autoimmune model of rheumatoid arthritis (RA). Ccr7-deficient mice were completely resistant to CIA and presented severely impaired antibody responses to collagen II (CII). Selective CCR7 expression on dendritic cells restored arthritis severity and anti-CII antibody titers. Prophylactic and therapeutic treatment of humanized CCR7 mice with anti-human CCR7 mAb 8H3-16A12 led to complete resistance to CIA and halted CIA progression, respectively. Our data demonstrate that CCR7 signaling is essential for the induction of CIA and identify CCR7 as a potential therapeutic target in RA.

The chemokine receptor CCR7 has a central role in regulating homing and positioning of T cells and DCs to lymph nodes (LNs) and participates in T-cell development and activation. In this study, we addressed the role of CCR7 signaling in T H 2 polarization and B-cell activation. We provide evidence that the lack of CCR7 drives the capacity of naïve CD4 1 T cells to polarize toward T H 2 cells. This propensity contributes to a lymph node environment in CCR7-deficent mice characterized by increased expression of IL-4 and increased frequency of T H 2 cells. We show that elevated IL-4 levels lead to B-cell activation characterized by up-regulated expression of MHC class II, CD23 and CD86. Activated B cells are in turn highly efficient in presenting antigen to CD41 T cells and thus potentially contribute to the T H 2 microenvironment. Taken together, our results support the idea of a CCR7-dependent patterning of T H 2 responses, with absent CCR7 signaling favoring T H 2 polarization, dislocation of T helper cells into the B-cell follicles and, as a consequence, B-cell activation. 48soluble factors. Moreover, in addition to the well-established role of CCR7 as a homing receptor directing the migration of cells into SLOs, increasing evidence suggests that CCR7-mediated signals contribute to other cellular processes such as modulation of cell proliferation, activation or differentiation [10][11][12].In the present study, we reveal the mechanisms that cause B-cell activation in the non-inflamed LNs in CCR7 À/À mice.

Immunosuppressive therapy (IST) is administered to patients with acquired hemophilia A (AHA) to eradicate autoantibodies against coagulation factor VIII (FVIII). Data from registries previously demonstrated that IST is often complicated by adverse events, in particular infections. This pilot study was set out to assess the feasibility of reduced-intensity, risk factor–stratified IST. We followed a single-center consecutive cohort of twenty-five patients with AHA receiving IST according to a new institutional treatment standard. Based on results from a previous study, GTH-AH 01/2020, patients were stratified into “poor risk” (FVIII < 1 IU/dl or inhibitor ≥ 20 Bethesda units (BU)/ml) or “good risk” (FVIII ≥ 1 IU/dl and inhibitor < 20 BU/ml). Outcomes were compared between the current cohort and the GTH registry as a historic control (n = 102). Baseline characteristics of the cohort were not different from the historic control. Partial remission, defined as FVIII recovered to > 50 IU/dl, was achieved by 68% of patients after a median time of 112 days, which was lower and significantly later than in the historic control (hazard ratio: 1.8, 95% confidence interval 1.2–2.8). Complete remission, overall survival, and frequency of fatal infections were not different. Grade 3 and 4 infections were more frequent. The impact of risk factors that was observed in the historic cohort was no longer apparent, as partial and complete remission and overall survival were similar in “good risk” and “poor risk” patients. In conclusion, reduced-intensity, risk factor–stratified IST is feasible in AHA but did not decrease the risk of infections and mortality in this cohort.