Jean-Marc Gombert

The pro-Th2 cytokine IL-33 directly interacts with invariant NKT and NK cells to induce IFN-gamma production.

IL‐33 has recently been identified as a cytokine endowed with pro‐Th2 functions, raising the question of its effect on invariant natural killer T cell (iNKT), which are potent IL‐4 producers. Here, we report a two‐fold increase of iNKT‐cell counts in spleen and liver after a 7‐day treatment of mice with IL‐33, which results from a direct effect, given that purified iNKT cells express the T1/ST2 receptor constitutively and respond to IL‐33 by in vitro expansion and functional activation. Conversely to the expected pro‐Th2 effect, IL‐33 induced a preferential increase in IFN‐γ rather than IL‐4 production upon TCR engagement that depended on endogenous IL‐12. Moreover, in combination with the pro‐inflammatory cytokine IL‐12, IL‐33 enhanced IFN‐γ production by both iNKT and NK cells. Taken together these data support the conclusion that IL‐33 can contribute as a co‐stimulatory factor to innate cellular immune responses.

Crystal-storing histiocytosis with renal Fanconi syndrome: pathological and molecular characteristics compared with classical myeloma-associated Fanconi syndrome

BACKGROUNDnCrystal-storing histiocytosis (CSH) is a poorly described complication of monoclonal gammopathy featuring histiocyte lysosomal storage of kappa light chain (kappa LC) crystals. Although CSH is usually associated with systemic manifestations, renal involvement is uncommon.nnnMETHODSnTo investigate the molecular mechanisms implicated in kappa LC crystallization, we performed immunopathological and molecular studies in three patients with CSH and renal Fanconi syndrome (CSH/FS). The V kappa sequences were determined, and resulting molecular models were compared with previously reported myeloma-associated FS kappa LC sequences.nnnRESULTSnAll patients presented with chronic tubulo-interstitial nephritis and renal FS with accumulation of monoclonal kappa LC crystals within proximal tubular cells. They showed peri-renal and interstitial infiltration by histiocytes containing eosinophilic crystalline inclusions (pseudo-pseudo-Gaucher cells). LC sequences were determined and assigned to their germline counterparts, in strong homology with previously reported myeloma-associated FS sequences. Comparison of CSH/FS V kappa domain 3D structures with the germline-encoded structures and those from patients with myeloma-associated FS underlined distinct hydrophobic residues exposed to the solvent in two patients, likely favouring the formation of a variant form of crystals that may further resist degradation after phagocytosis.nnnCONCLUSIONnAlthough CSH/FS and myeloma-associated FS are closely related disorders, peculiar mutations in the V domains of CSH/FS monoclonal kappa LCs, different from those in myeloma-associated FS, may account for crystal morphology, predominant accumulation within histiocytes and multiple organ involvement in CSH.

A natural protective function of invariant NKT cells in a mouse model of innate‐cell‐driven lung inflammation

Activation of invariant natural killer T (iNKT) cells by treatment with their α‐galactosyl ceramide ligand provides therapeutic benefits in several immune inflammatory settings. Given the artificial nature of this stimulation, the natural regulatory functions of iNKT remain uncertain. Addressing this issue in a mouse model of innate‐cell‐driven lung inflammation induced by the cytokine/alarmin IL‐33 that targets iNKT cells, we found that eosinophil and neutrophil recruitment was markedly increased in treated iNKT cell‐deficient (Jα18 KO) mice, as was the local production of eotaxin and keratinocyte chemoattractant chemokines. By contrast, lung inflammation decreased after adoptive transfer of iNKT cells, which restored the WT inflammatory response in Jα18 KO mice. Finally, we established that this natural anti‐inflammatory function of iNKT cells depends on their IFN‐γ production and on endogenous IL‐12. Our study provides the first evidence of a protective role of iNKT cells during lung inflammation that does not require pharmacological TCR engagement.

The HOXB4 Homeoprotein Promotes the Ex Vivo Enrichment of Functional Human Embryonic Stem Cell-Derived NK Cells

Human embryonic stem cells (hESCs) can be induced to differentiate into blood cells using either co-culture with stromal cells or following human embryoid bodies (hEBs) formation. It is now well established that the HOXB4 homeoprotein promotes the expansion of human adult hematopoietic stem cells (HSCs) but also myeloid and lymphoid progenitors. However, the role of HOXB4 in the development of hematopoietic cells from hESCs and particularly in the generation of hESC-derived NK-progenitor cells remains elusive. Based on the ability of HOXB4 to passively enter hematopoietic cells in a system that comprises a co-culture with the MS-5/SP-HOXB4 stromal cells, we provide evidence that HOXB4 delivery promotes the enrichment of hEB-derived precursors that could differentiate into fully mature and functional NK. These hEB-derived NK cells enriched by HOXB4 were characterized according to their CMH class I receptor expression, their cytotoxic arsenal, their expression of IFNγ and CD107a after stimulation and their lytic activity. Furthermore our study provides new insights into the gene expression profile of hEB-derived cells exposed to HOXB4 and shows the emergence of CD34+CD45RA+ precursors from hEBs indicating the lymphoid specification of hESC-derived hematopoietic precursors. Altogether, our results outline the effects of HOXB4 in combination with stromal cells in the development of NK cells from hESCs and suggest the potential use of HOXB4 protein for NK-cell enrichment from pluripotent stem cells.

Les fonctions innées des lymphocytes T CD8 dans la lutte contre le cancer

HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L’archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. [The CD8+ T cell innate function in the war against cancer]. Alice Barbarin, André Herbelin, Jean-Marc Gombert

Hépatite fulminante compliquant une maladie de dépôts de chaînes lourdes d’immunoglobulines monoclonales de type Randall

Introduction Le syndrome de Randall, egalement appele «xa0monoclonal immunoglobulin deposition diseasexa0», se definit par la presence de depots non organises d’immunoglobulines monoclonales. Dans de rares cas, les depots sont constitues d’une chaine lourde isolee (heavy chain deposition disease, HCDD). L’atteinte renale est quasi constante. Les manifestations extra-renales, souvent asymptomatiques, sont de frequence mal connue. Nous rapportons une forme rare de HCDD avec atteinte hepatique severe. Observation Un patient de 85xa0ans est hospitalise pour ictere et perte de 10xa0kg en 3xa0mois. A l’admission, il presente des œdemes des membres inferieurs et une hepatomegalie. Le bilan biologique revele une cholestase icterique (phosphatases alcalinesxa0=xa010xa0N, bilirubine conjugueexa0=xa03xa0N), une cytolyse hepatique (transaminasesxa0=xa02xa0N), une hypo-albuminemie a 15xa0g/L et une bi-cytopenie. L’immunofixation detecte une proteine monoclonale IgGλ. La creatininemie est a 73xa0μmol/L. Le bilan urinaire met en evidence une proteinurie a 4,6xa0g/j (47xa0% d’albumine, Bence Jonesxa0λ). Le myelogramme revele 23xa0% de plasmocytes dystrophiques. Une chimiotherapie par bortezomibxa0+xa0dexamethasone est debutee. L’evolution est rapidement defavorable, avec degradation du bilan hepatique et insuffisance renale aigue. Le patient decede 5xa0jours plus tard d’une hepatite fulminante. La biopsie hepatique post-mortem montre des depots eosinophiles, PAS (+), rouge Congo (–), localises au niveau des espaces de Disse et des membranes basales des canaux biliaires. En immunofluorescence, les depots sont constitues d’une chaine lourde γ1xa0deletee de son premier domaine constant (CH1) sans chaine legere associee. L’etude du serum en immunoblot confirme la presence d’une chaine lourde γ1xa0libre tronquee. Conclusion Ce premier cas d’HCDD avec hepatite fulminante souligne l’importance de la recherche des manifestations extra-renales, qui peuvent parfois menacer le pronostic vital. Les mecanismes physiopathologiques impliques dans cette maladie demeurent mal elucides. Si la deletion du CH1xa0facilite la secretion d’une chaine lourde libre, les caracteristiques du domaine variable semblent etre impliquees dans l’apparition des depots tissulaires.