Molecular interactions controlling immune homeostasis in the marginal zone

The immune system serves to eliminate harmful microorganisms and cancer cells from the body. When these agents invade the blood stream, rapid detection and response by immune cells is crucial to protect the host. To achieve this, different immune cells such as B cells and dendritic cells are organized in a unique structure in the spleen where blood is filtered: the marginal zone. Generally speaking, marginal zone B cells will rapidly produce antibodies that neutralize harmful bacteria, while dendritic cells will mount a long-lasting and tailored immune response against a broad spectrum of agents. However, the precise factors that control the development and function of cells in the marginal zone remain poorly characterized. A better understanding of the biology of cells in this compartment may lead to novel approaches in the treatment of invasive infections, autoimmune disease and cancer. In this thesis, I report how the development of B cells and dendritic cells in the marginal zone depends on the relatively unknown protein TAOK3. In addition, we found that innate lymphoid cells, another type of immune cells, provided biological signals that were crucial for the development of marginal zone dendritic cells. Furthermore, we revealed that dendritic cells in the spleen protect against a chronic myeloid leukemia-like disease through the expression of the protein IRF8. In summary, we have uncovered novel biological factors that regulate the development and function of immune cells in the spleen

The diagnostic value of SE MRI and DWI of the spine in patients with monoclonal gammopathy of undetermined significance, smouldering myeloma and multiple myeloma

Objectives: To evaluate DWI of the bone marrow in the differentiation of monoclonal gammopathy of undetermined significance (MGUS), smouldering myeloma (SMM) and multiple myeloma (MM). Methods The retrospective study includes 64 patients with MGUS, 27 with SMM, 64 with new MM and 12 controls. Signal intensity (SI) of spinal SE-MRI and DWI (b0-1000) as well as apparent diffusion coefficients (ADC) were measured in the T10 and L3. Qualitative assessment of b-images was performed by one experienced radiologist. Results: ADC600 and ADC1000 are the best ADC values in differentiating patient groups (p50 % (p=0.001). Only SIT2 for L3 can differentiate MGUS from SMM (p=0.044) and PC%0-10 from PC%10-25 (p=0.033). Qualitative interpretation of b1000 images allows differentiating MM patients from those with MGUS or SMM (p<0.001). Conclusions: Spinal SE-MRI can differentiate among MGUS, SMM, MM and control subjects. DWI based on the SI on b1000 images and ADC values is increased in MM compared to MGUS and SMM. Qualitative assessment of b-images can differentiate MM from MGUS or SMM. Key points: - ADC values are higher in patients with MM compared to MGUS - DWI parameters change late in disease evolution - DWI is sensitive but not specific in diagnosing patients with MM - Qualitative DWI assessment is good in detecting myeloma patient

The STE20 kinase TAOK3 controls the development of house dust mite-induced asthma in mice

Background: The most common endotype of asthma is type 2-high asthma, which is sometimes driven by adaptive allergen-specific TH2 lymphocytes that react to allergens presented by dendritic cells (DCs), or sometimes by an innate immune response dominated by type 2 innate lymphocytes (ILC2s). Understanding the underlying pathophysiology of asthma is essential to improve patient-tailored therapy. The STE20 kinase thousand-and-one kinase 3 (TAOK3) controls key features in the biology of DCs and lymphocytes, but to our knowledge, its potential usefulness as a target for asthma therapy has not yet been addressed. Objective: We examined if and how loss of Taok3 affects the development of house dust mite (HDM)-driven allergic asthma in an in vivo mouse model. Methods: Wild-type Taok3+/+ and gene-deficient Taok3-/- mice were sensitized and challenged with HDM, and bronchoalveolar lavage fluid composition, mediastinal lymph node cytokine production, lung histology, and bronchial hyperreactivity measured. Conditional Taok3fl/fl mice were crossed to tissue- and cell-specific specific deletor Cre mice to understand how Taok3 acted on asthma susceptibility. Kinase-dead (KD) Taok3KD mice were generated to probe for the druggability of this pathway. Activation of HDM-specific T cells was measured in adoptively transferred HDM-specific T-cell receptor-transgenic CD4+ T cells. ILC2 biology was assessed by in vivo and in vitro IL-33 stimulation assays in Taok3-/- and Taok3+/+, Taok3KD, and Red5-Cre Taok3fl/fl mice. Results: Taok3-/- mice failed to mount salient features of asthma, including airway eosinophilia, TH2 cytokine production, IgE secretion, airway goblet cell metaplasia, and bronchial hyperreactivity compared to controls. This was due to intrinsic loss of Taok3 in hematopoietic and not epithelial cells. Loss of Taok3 resulted in hampered HDM-induced lung DC migration to the draining lymph nodes and defective priming of HDM-specific TH2 cells. Strikingly, HDM and IL-33-induced ILC2 proliferation and function were also severely affected in Taok3-deficient and Taok3KD mice. Conclusions: Absence of Taok3 or loss of its kinase activity protects from HDM-driven allergic asthma as a result of defects in both adaptive DC-mediated TH2 activation and innate ILC2 function. This identifies Taok3 as an interesting drug target, justifying further testing as a new treatment for type 2-high asthma

TAO-kinase 3 governs the terminal differentiation of conventional dendritic cells

Antigen-presenting conventional dendritic cells (cDCs) are broadly divided into type 1 and type 2 subsets that further adapt their phenotype and function to perform specialized tasks in the immune system. The precise signals controlling tissue-specific adaptation and differentiation of cDCs are currently poorly understood. We found that mice deficient in the Ste20 kinase Thousand and One Kinase 3 (TAOK3) lacked terminally differentiated ESAM(+) CD4(+) cDC2s in the spleen and failed to prime CD4(+) T cells in response to allogeneic red-blood-cell transfusion. These NOTCH2and ADAM10dependent cDC2s were absent selectively in the spleen, but not in the intestine of Taok3(-/-) and CD11c-cre Taok3(fl/fl) mice. The loss of splenic ESAM(+) cDC2s was cell-intrinsic and could be rescued by conditional overexpression of the constitutively active NOTCH intracellular domain in CD11c-expressing cells. Therefore, TAOK3 controls the terminal differentiation of NOTCH2-dependent splenic cDC2s

ILC3s control splenic cDC homeostasis via lymphotoxin signaling

International audienceThe spleen contains a myriad of conventional dendritic cell (cDC) subsets that protect against systemic pathogen dissemination by bridging antigen detection to the induction of adaptive immunity. How cDC subsets differentiate in the splenic environment is poorly understood. Here, we report that LTα 1 β 2-expressing Rorgt + ILC3s, together with B cells, control the splenic cDC niche size and the terminal differentiation of Sirpα + CD4 + Esam + cDC2s, independently of the microbiota and of bone marrow pre-cDC output. Whereas the size of the splenic cDC niche depended on lymphotoxin signaling only during a restricted time frame, the homeostasis of Sirpα + CD4 + Esam + cDC2s required continuous lymphotoxin input. This latter property made Sirpα + CD4 + Esam + cDC2s uniquely susceptible to pharmacological interventions with LTβR agonists and antagonists and to ILC reconstitution strategies. Together, our findings demonstrate that LTα 1 β 2-expressing Rorgt + ILC3s drive splenic cDC differentiation and highlight the critical role of ILC3s as perpetual regulators of lymphoid tissue homeostasis

IRF8 Transcription Factor Controls Survival and Function of Terminally Differentiated Conventional and Plasmacytoid Dendritic Cells, Respectively

International audienceInterferon regulatory factor-8 (IRF8) has been proposed to be essential for development of monocytes, plasmacytoid dendritic cells (pDCs) and type 1 conventional dendritic cells (cDC1s) and remains highly expressed in differentiated DCs. Transcription factors that are required to maintain the identity of terminally differentiated cells are designated `' terminal selectors.'' Using BM chimeras, conditional Irf8(fl/fl) mice and various promotors to target Cre recombinase to different stages of monocyte and DC development, we have identified IRF8 as a terminal selector of the cDC1 lineage controlling survival. In monocytes, IRF8 was necessary during early but not late development. Complete or late deletion of IRF8 had no effect on pDC development or survival but altered their phenotype and gene-expression profile leading to increased T cell stimulatory function but decreased type 1 interferon production. Thus, IRF8 differentially controls the survival and function of terminally differentiated monocytes, cDC1s, and pDCs