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In addition to triggering humoral responses, conventional B cells have been described in vitro to cross-present exogenous antigens activating naïve CD8 T cells. Nevertheless, the way B cells capture these exogenous antigens and the physiological roles of B cell-mediated cross-presentation remain poorly explored. Here, we show that B cells capture bacteria by trans-phagocytosis from previously infected dendritic cells (DC) when they are in close contact. Bacterial encounter “instructs” the B cells to acquire antigen cross-presentation abilities, in a process that involves autophagy. Bacteria-instructed B cells, henceforth referred to as BacB cells, rapidly degrade phagocytosed bacteria, process bacterial antigens and cross-prime naïve CD8 T cells which differentiate into specific cytotoxic cells that efficiently control bacterial infections. Moreover, a proof-of-concept experiment shows that BacB cells that have captured bacteria expressing tumor antigens could be useful as novel cellular immunotherapies against cancer.

Diffuse large B-cell lymphoma (DLBCL) is the most common Non-Hodgkin's lymphoma, accounting for the 40% of diagnosed cases worldwide. The heterogeneous nature of this disease is one of its main features and is directly related to the prognosis shown by the patients. There are many indicators linked to the development of the pathology but the most important one is the subtype of DLBCL present in the patient. The most extended classification distinguishes between germinal centre B-cell-like (GCB) DLBCL and activated B-cell-like (ABC) DLBCL. Both subtypes are defined by the differences detected in their genetic profile, that delineates not only the subtype but also the major mutations associated with each of them. ABC DLBCL associates with a worse prognosis, so specific compounds have been added to the treatment for fighting ABC DLBCL. Ibrutinib is one of those compounds, inhibitor of the kinase activity of Btk. ABC DLBCL neoplastic cells depend for their survival on the activation of the NF- kB pathway via Btk. Ibrutinib promotes neoplastic cell death by inhibiting Btk activity, and therefore NF- kB route. It has been shown to be effective in the treatment of ABC DLBCL, however, its effectiveness is reduced in the presence of the L265P mutation in the adaptor protein MyD88. This mutation allows MyD88 constitutive activation, promoting the assembly of the Btk signalosome and thus modulating Btk activity.The expression of the chemokine receptor CXCR4 is also related to a worse prognosis of the DLBCL. High CXCR4 expression levels at the cell surface are associated with a more aggressive nature of the tumour due to its involvement in cell migration and adhesion events. In addition, there is controversy about the involvement of Btk in the CXCR4-mediated functions.Taking into account the relevance of Btk and MyD88 in the development of ABC DLBCL, and that of CXCR4 in DLBCL, this work will evaluate the relationship between the three proteins in the molecular environment of t

The ability of a cell to migrate, adhere and change its morphology is determinant to develop its functions; these capacities reach their maximum relevance in immune cells. For an efficient immune response, immune cells must localize in the right place at the right time; that implies crossing tissue barriers and migrating in the interstitial space of the tissues at high velocities. The dependency on trafficking abilities is even higher for B cells, one of the arms of the adaptive immune system, considering that they must encounter specific antigen for their clonal receptor in the enormous tissue volume of the secondary lymphoid organs (spleen, lymph nodes, Peyer patches). The regulated interplay between cell motililty and cell adhesion allows B cells to reach distinct lymphoid tissues and, within them, to explore the stromal cell networks where antigen might be exposed. In this meeting-invited review, I summarize the current knowledge on the molecular cues and mechanisms that shapes B cell dynamics at the initial phase of the humoral immune response, including homeostatic chemoatractants and innate/inflamatory stimuli. I also revised the B cell behaviour alterations caused by BCR recognition of antigen and the molecular mechanisms involved.

Efficient generation of antibodies by B cells is one of the prerequisites of protective immunity. B cell activation by cognate antigens via B cell receptors (BCRs), or pathogen-associated molecules through pattern-recognition receptors, such as Toll-like receptors (TLRs), leads to transcriptional and metabolic changes that ultimately transform B cells into antibody-producing plasma cells or memory cells. BCR signaling and a number of steps downstream of it rely on coordinated action of cellular membranes and the actin cytoskeleton, tightly controlled by concerted action of multiple regulatory proteins, some of them exclusive to B cells. Here, we dissect the role of Missing-In-Metastasis (MIM), or Metastasis suppressor 1 (MTSS1), a cancer-associated membrane and actin cytoskeleton regulating protein, in B cell-mediated immunity by taking advantage of MIM knockout mouse strain. We show undisturbed B cell development and largely normal composition of B cell compartments in the periphery. Interestingly, we found that MIM−/− B cells are defected in BCR signaling in response to surface-bound antigens but, on the other hand, show increased metabolic activity after stimulation with LPS or CpG. In vivo, MIM knockout animals exhibit impaired IgM antibody responses to immunization with T cell-independent antigen. This study provides the first comprehensive characterization of MIM in B cells, demonstrates its regulatory role for B cell-mediated immunity, as well as proposes new functions for MIM in tuning receptor signaling and cellular metabolism, processes, which may also contribute to the poorly understood functions of MIM in cancer.

A current challenge in cell motility studies is to understand the molecular and physical mechanisms that govern chemokine receptor nanoscale organization at the cell membrane, and their influence on cell response. Using single-particle tracking and super-resolution microscopy, we found that the chemokine receptor CXCR4 forms basal nanoclusters in resting T cells, whose extent, dynamics, and signaling strength are modulated by the orchestrated action of the actin cytoskeleton, the co-receptor CD4, and its ligand CXCL12. We identified three CXCR4 structural residues that are crucial for nanoclustering and generated an oligomerization-defective mutant that dimerized but did not form nanoclusters in response to CXCL12, which severely impaired signaling. Overall, our data provide new insights to the field of chemokine biology by showing that receptor dimerization in the absence of nanoclustering is unable to fully support CXCL12-mediated responses, including signaling and cell function in vivo