Les cellules de Langerhans

Les cellules de Langerhans (CL) de l’épiderme et des épithéliums pluristratifiés appartiennent au système immunitaire. Ces cellules ont un éventail de fonctions très différentes, avec des implications qui vont bien au-delà de la peau, en raison de leurs propriétés de migration qui leur permettent d’informer les lymphocytes T dans les ganglions drainants. Les CL furent longtemps considérées comme les acteurs principaux de la réponse immune dans les maladies infectieuses, tel le sida, l’allergie, les réactions inflammatoires chroniques, les rejets de tumeur ou la transplantation. Découvertes il y a près de 140 ans, elles restent cependant énigmatiques par de nombreux aspects, et leur rôle précis dans le déclenchement de la réaction immunitaire cutanée ou dans l’établissement d’une tolérance aux composants du soi reste controversé.Epidermal Langerhans cells, a constituent of the skin immune system, have a spectrum of different functions with implications that extend far beyond the skin. They have the potential to internalize particulate agents and macromolecules, and display migratory properties that endow them with the unique capacity to journey between skin and draining lymph nodes where they encounter antigen-specific T lymphocytes. In addition, LC are considered to play a pivotal role in infectious disease such as Aids, allergy, chronic inflammatory reactions, tumor rejections or transplantation. Herein, we will review the features of Langerhans cells, emphasizing characteristics representative of their life-cycle stages that occur within the skin

Cold Tumors: A Therapeutic Challenge for Immunotherapy

Therapeutic monoclonal antibodies targeting immune checkpoints (ICPs) have changed the treatment landscape of many tumors. However, response rate remains relatively low in most cases. A major factor involved in initial resistance to ICP inhibitors is the lack or paucity of tumor T cell infiltration, characterizing the so-called “cold tumors.” In this review, we describe the main mechanisms involved in the absence of T cell infiltration, including lack of tumor antigens, defect in antigen presentation, absence of T cell activation and deficit of homing into the tumor bed. We discuss then the different therapeutic approaches that could turn cold into hot tumors. In this way, specific therapies are proposed according to their mechanism of action. In addition, ‘‘supra-physiological’’ therapies, such as T cell recruiting bispecific antibodies and Chimeric Antigen Receptor (CAR) T cells, may be active regardless of the mechanism involved, especially in MHC class I negative tumors. The determination of the main factors implicated in the lack of preexisting tumor T cell infiltration is crucial for the development of adapted algorithms of treatments for cold tumors

Circulating and Hepatic BDCA1+, BDCA2+, and BDCA3+ Dendritic Cells Are Differentially Subverted in Patients With Chronic HBV Infection

Background and aims: Chronic hepatitis B virus (HBV) infection is a major health burden potentially evolving toward cirrhosis and hepatocellular carcinoma. HBV physiopathology is strongly related to the host immunity, yet the mechanisms of viral evasion from immune-surveillance are still misunderstood. The immune response elicited at early stages of viral infection is believed to be important for subsequent disease outcome. Dendritic cells (DCs) are crucial immune sentinels which orchestrate antiviral immunity, which offer opportunity to pathogens to subvert them to escape immunity. Despite the pivotal role of DCs in orientating antiviral responses and determining the outcome of infection, their precise involvement in HBV pathogenesis is not fully explored.Methods: One hundred thirty chronically HBV infected patients and 85 healthy donors were enrolled in the study for blood collection, together with 29 chronically HBV infected patients and 33 non-viral infected patients that were included for liver biopsy collection. In a pioneer way, we investigated the phenotypic and functional features of both circulating and intrahepatic BDCA1+ cDC2, BDCA2+ pDCs, and BDCA3+ cDC1 simultaneously in patients with chronic HBV infection by designing a unique multi-parametric flow cytometry approach.Results: We showed modulations of the frequencies and basal activation status of blood and liver DCs associated with impaired expressions of specific immune checkpoints and TLR molecules on circulating DC subsets. Furthermore, we highlighted an impaired maturation of circulating and hepatic pDCs and cDCs following stimulation with specific TLR agonists in chronic HBV patients, associated with drastic dysfunctions in the capacity of circulating DC subsets to produce IL-12p70, TNFα, IFNα, IFNλ1, and IFNλ2 while intrahepatic DCs remained fully functional. Most of these modulations correlated with HBsAg and HBV DNA levels.Conclusion: We highlight potent alterations in the distribution, phenotype and function of all DC subsets in blood together with modulations of intrahepatic DCs, revealing that HBV may hijack the immune system by subverting DCs. Our findings provide innovative insights into the immuno-pathogenesis of HBV and the mechanisms of virus escape from immune control. Such understanding is promising for developing new therapeutic strategies restoring an efficient immune control of the virus

CARACTERISATION DE RECEPTEURS D'ENDOCYTOSE EXPRIMES PAR LES CELLULES DENDRITIQUES HUMAINES ET IDENTIFICATION DE LA MOLECULE LANGERINE

LYON1-BU Santé (693882101) / SudocPARIS-BIUM (751062103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Mécanismes de reconnaissance des signaux de danger par les cellules dendritiques de la peau et des muqueuses (application à l'étude de l'infection par le VIH dans un modèle de muqueuse vaginale humaine intégrant des cellules de Langerhans)

A l interface entre l immunité innée et adaptative, les cellules dendritiques (DC) jouent un rôle clef dans l induction de la réponse immunitaire. Dans la peau et les muqueuses, deux types de DC sont présentes : les cellules de Langerhans (CL) dans l épiderme et les épithéliums et les DC dans le derme et le chorion (DDC). Dans une première partie, nous nous sommes intéressées aux DDC humaines, qui contrairement aux CL, restent méconnues. Les principales caractéristiques phénotypiques et fonctionnelles des DDC humaines isolées ex vivo à partir de derme humain ont été étudiées et notamment leur expression des récepteurs de l immunité innée tels que les Toll Like Receptor (TLR) ou les lectines de type C. En parallèle, le profil d expression des TLR par les CL humaines fraîchement isolées a également été analysé. Ainsi, par l expression différentielle des récepteurs de l immunité innée, les CL et les DDC joueraient chacune un rôle spécifique dans l immunité de la peau et des muqueuses. Au sein des muqueuses génitales, plus particulièrement, elles interviennent dans la transmission de l infection par le Virus de l Immunodéficience Humaine (VIH). Dans une seconde partie, nous avons examiné les événements précoces dans la transmission du VIH à travers la muqueuse vaginale ainsi que le rôle des CL dans ce mécanisme. Pour cela, nous avons développé, à partir de cellules primaires humaines, un modèle de muqueuse vaginale reconstruite intégrant des CL. Nos travaux ont permis de mieux caractériser les populations de DC de la peau et des muqueuses ainsi que leur potentiel rôle dans l immunité périphérique, ce qui devrait être utile pour le développement de futures thérapies anti-infectieuses dans lesquelles de telles DC sont cibléesResiding at the interface between innate and adaptative immunity, dendritic cells (DC), and particularly Langerhans cells (LC) of epidermis and epithelia and DC of dermis or lamina propria (DDC), play a key role in the initiation of immune responses. In a first time, we analyzed the main phenotypic and functional characteristics of freshly isolated human dermal DC, as they were still barely studied contrary to human LC. We focused especially on the expression of innate receptors such as Toll Like Receptors (TLR) and C-type lectins. In parallel, TLR expression was also assessed in freshly isolated human LC. Thus, by their differential expression of innate receptors, LC and DDC would play each a specific role in cutaneous and mucosal immunity. Notably, within genital mucosa, they contribute to the transmission of HIV infection. Therefore, in a second time, we examined the early events in HIV entry into the vaginal mucosa and the precise role of LC in this transmission. For that purpose, we developed an in vitro model of vaginal mucosa, using human primary vaginal cells, in which LC could be integrated. In conclusion, we provided here a better characterisation of human LC and DDC as well as their potential function in peripheral immunity that should be useful for the development of future immunotherapies in which such DC are targetedLYON1-BU.Sciences (692662101) / SudocSudocFranceF

Poly(I:C)-Treated human langerhans cells promote the differentiation of CD4+ T cells producing IFN-gamma and IL-10.

International audienceEpidermal Langerhans cells (LCs) are the first dendritic cells to encounter skin pathogens. However, their function has recently been challenged, especially in the initiation of T-cell responses to viral antigens. We have previously reported that fresh immature human LCs express mRNA encoding TLR3. Here we analyze the response of highly purified human LCs to poly(I:C), a synthetic mimetic of viral dsRNA recognized by TLR3. We show that LCs exposed for 2 days to poly(I:C) under serum-free conditions up-regulated co-stimulatory molecules, a process associated with increased allostimulatory capacity. Furthermore, poly(I:C) significantly enhanced LC survival and induced them to produce CXCL10, IL-6, and IL-12 p40. Bioactive IL-12 p70, IL-1beta, IL-15, IL-18, and IL-23 were never detected, even after CD40 ligation. LC incubation in the presence of bafilomycin completely reversed the effect of poly(I:C) on LC phenotypic activation and survival, indicating that endosomal TLR3 is involved in this process. Most interestingly, we report here that poly(I:C)-treated LCs favored alloreactive CD4(+) T-cell differentiation toward a Th1 profile and concomitant differentiation of IL-10-producing CD4(+) T cells that might limit, at another time, the inflammatory response and subsequent tissue damage

Human Tumor-Infiltrating Dendritic Cells: From In Situ Visualization to High-Dimensional Analyses

The interaction between tumor cells and the immune system is considered to be a dynamic process. Dendritic cells (DCs) play a pivotal role in anti-tumor immunity owing to their outstanding T cell activation ability. Their functions and activities are broad ranged, triggering different mechanisms and responses to the DC subset. Several studies identified in situ human tumor-infiltrating DCs by immunostaining using a limited number of markers. However, considering the heterogeneity of DC subsets, the identification of each subtype present in the immune infiltrate is essential. To achieve this, studies initially relied on flow cytometry analyses to provide a precise characterization of tumor-associated DC subsets based on a combination of multiple markers. The concomitant development of advanced technologies, such as mass cytometry or complete transcriptome sequencing of a cell population or at a single cell level, has provided further details on previously identified populations, has unveiled previously unknown populations, and has finally led to the standardization of the DCs classification across tissues and species. Here, we review the evolution of tumor-associated DC description, from in situ visualization to their characterization with high-dimensional technologies, and the clinical use of these findings specifically focusing on the prognostic impact of DCs in cancers