Tim Worbs

Bio: Tim Worbs is an academic researcher from Hannover Medical School. The author has contributed to research in topics: T cell & C-C chemokine receptor type 7. The author has an hindex of 21, co-authored 30 publications receiving 5042 citations.

Rapid leukocyte migration by integrin-independent flowing and squeezing

Abstract: All metazoan cells carry transmembrane receptors of the integrin family, which couple the contractile force of the actomyosin cytoskeleton to the extracellular environment In agreement with this principle, rapidly migrating leukocytes use integrin-mediated adhesion when moving over two-dimensional surfaces As migration on two-dimensional substrates naturally overemphasizes the role of adhesion, the contribution of integrins during three-dimensional movement of leukocytes within tissues has remained controversial We studied the interplay between adhesive, contractile and protrusive forces during interstitial leukocyte chemotaxis in vivo and in vitro We ablated all integrin heterodimers from murine leukocytes, and show here that functional integrins do not contribute to migration in three-dimensional environments Instead, these cells migrate by the sole force of actin-network expansion, which promotes protrusive flowing of the leading edge Myosin II-dependent contraction is only required on passage through narrow gaps, where a squeezing contraction of the trailing edge propels the rigid nucleus

Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions

Abstract: Chemokine receptor CX3CR1+ dendritic cells (DCs) have been suggested to sample intestinal antigens by extending transepithelial dendrites into the gut lumen. Other studies identified CD103+ DCs in the mucosa, which, through their ability to synthesize retinoic acid (RA), appear to be capable of generating typical signatures of intestinal adaptive immune responses. We report that CD103 and CX3CR1 phenotypically and functionally characterize distinct subsets of lamina propria cells. In contrast to CD103+ DC, CX3CR1+ cells represent a nonmigratory gut-resident population with slow turnover rates and poor responses to FLT-3L and granulocyte/macrophage colony-stimulating factor. Direct visualization of cells in lymph vessels and flow cytometry of mouse intestinal lymph revealed that CD103+ DCs, but not CX3CR1-expressing cells, migrate into the gut draining mesenteric lymph nodes (LNs) under steady-state and inflammatory conditions. Moreover, CX3CR1+ cells displayed poor T cell stimulatory capacity in vitro and in vivo after direct injection of cells into intestinal lymphatics and appeared to be less efficient at generating RA compared with CD103+ DC. These findings indicate that selectively CD103+ DCs serve classical DC functions and initiate adaptive immune responses in local LNs, whereas CX3CR1+ populations might modulate immune responses directly in the mucosa and serve as first line barrier against invading enteropathogens.

Oral tolerance originates in the intestinal immune system and relies on antigen carriage by dendritic cells.

Abstract: Oral tolerance induction is a key feature of intestinal immunity, generating systemic nonresponsiveness to ingested antigens. In this study, we report that orally applied soluble antigens are exclusively recognized in the intestinal immune system, particularly in the mesenteric lymph nodes. Consequently, the initiation of oral tolerance is impeded by mesenteric lymphadenectomy. Small bowel transplantation reveals that mesenteric lymph nodes require afferent lymph to accomplish the recognition of orally applied antigens. Finally, oral tolerance cannot be induced in CCR7-deficient mice that display impaired migration of dendritic cells from the intestine to the mesenteric lymph nodes, suggesting that immunologically relevant antigen is transported in a cell-bound fashion. These results demonstrate that antigen transport via afferent lymphatics into the draining mesenteric lymph nodes is obligatory for oral tolerance induction, inspiring new therapeutic strategies to exploit oral tolerance induction for the prevention and treatment of autoimmune diseases.

Dendritic cell migration in health and disease

Abstract: Dendritic cells (DCs) are potent and versatile antigen-presenting cells, and their ability to migrate is key for the initiation of protective pro-inflammatory as well as tolerogenic immune responses. Recent comprehensive studies have highlighted the importance of DC migration in the maintenance of immune surveillance and tissue homeostasis, and also in the pathogenesis of a range of diseases. In this Review, we summarize the anatomical, cellular and molecular factors that regulate the migration of different DC subsets in health and disease. In particular, we focus on new insights concerning the role of migratory DCs in the pathogenesis of diseases of the skin, intestine, lung, and brain, as well as in autoimmunity and atherosclerosis.

CCR7 ligands stimulate the intranodal motility of T lymphocytes in vivo.

Abstract: In contrast to lymphocyte homing, little is known about molecular cues controlling the motility of lymphocytes within lymphoid organs. Applying intravital two-photon microscopy, we demonstrate that chemokine receptor CCR7 signaling enhances the intranodal motility of CD4+ T cells. Compared to wild-type (WT) cells, the average velocity and mean motility coefficient of adoptively transferred CCR7-deficient CD4+ T lymphocytes in T cell areas of WT recipients were reduced by 33 and 55%, respectively. Both parameters were comparably reduced for WT T lymphocytes migrating in T cell areas of plt/plt mice lacking CCR7 ligands. Importantly, systemic application of the CCR7 ligand CCL21 was sufficient to rescue the motility of WT T lymphocytes inside T cell areas of plt/plt recipients. Comparing the movement behavior of T cells in subcapsular areas that are devoid of detectable amounts of CCR7 ligands even in WT mice, we failed to reveal any differences between WT and plt/plt recipients. Furthermore, in both WT and plt/plt recipients, highly motile T cells rapidly accumulated in the subcapsular region after subcutaneous injection of the CCR7 ligand CCL19. Collectively, these data identify CCR7 and its ligands as important chemokinetic factors stimulating the basal motility of CD4+ T cells inside lymph nodes in vivo.

Development of Monocytes, Macrophages, and Dendritic Cells

Abstract: Monocytes and macrophages are critical effectors and regulators of inflammation and the innate immune response, the immediate arm of the immune system. Dendritic cells initiate and regulate the highly pathogen-specific adaptive immune responses and are central to the development of immunologic memory and tolerance. Recent in vivo experimental approaches in the mouse have unveiled new aspects of the developmental and lineage relationships among these cell populations. Despite this, the origin and differentiation cues for many tissue macrophages, monocytes, and dendritic cell subsets in mice, and the corresponding cell populations in humans, remain to be elucidated.

A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β– and retinoic acid–dependent mechanism

Abstract: Foxp3+ regulatory T (T reg) cells play a key role in controlling immune pathological re actions. Many develop their regulatory activity in the thymus, but there is also evidence for development of Foxp3+ T reg cells from naive precursors in the periphery. Recent studies have shown that transforming growth factor (TGF)-β can promote T reg cell development in culture, but little is known about the cellular and molecular mechanisms that mediate this pathway under more physiological conditions. Here, we show that after antigen activation in the intestine, naive T cells acquire expression of Foxp3. Moreover, we identify a population of CD103+ mesenteric lymph node dendritic cells (DCs) that induce the devel opment of Foxp3+ T reg cells. Importantly, promotion of T reg cell responses by CD103+ DCs is dependent on TGF-β and the dietary metabolite, retinoic acid (RA). These results newly identify RA as a cofactor in T reg cell generation, providing a mechanism via which functionally specialized gut-associated lymphoid tissue DCs can extend the repertoire of T reg cells focused on the intestine.

The extracellular matrix: A dynamic niche in cancer progression

Abstract: The local microenvironment, or niche, of a cancer cell plays important roles in cancer development. A major component of the niche is the extracellular matrix (ECM), a complex network of macromolecules with distinctive physical, biochemical, and biomechanical properties. Although tightly controlled during embryonic development and organ homeostasis, the ECM is commonly deregulated and becomes disorganized in diseases such as cancer. Abnormal ECM affects cancer progression by directly promoting cellular transformation and metastasis. Importantly, however, ECM anomalies also deregulate behavior of stromal cells, facilitate tumor-associated angiogenesis and inflammation, and thus lead to generation of a tumorigenic microenvironment. Understanding how ECM composition and topography are maintained and how their deregulation influences cancer progression may help develop new therapeutic interventions by targeting the tumor niche.