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Human CD8 tumor-infiltrating lymphocytes (TILs) with impaired effector functions and PD-1 expression are categorized as exhausted. However, the exhaustion-like features reported in TILs might stem from their activation rather than the consequence of T cell exhaustion itself. Using CRISPR-Cas9 and lentiviral overexpression in CD8 T cells from non-cancerous donors, we show that the T cell receptor (TCR)-induced transcription factor interferon regulatory factor 4 (IRF4) promotes cell proliferation and PD-1 expression and hampers effector functions and expression of nuclear factor κB (NF-κB)-regulated genes. While CD8 TILs with impaired interferon γ (IFNγ) production exhibit activation markers IRF4 and CD137 and exhaustion markers thymocyte selection associated high mobility group box (TOX) and PD-1, activated T cells in patients with COVID-19 do not demonstrate elevated levels of TOX and PD-1. These results confirm that IRF4+TILs are exhausted rather than solely activated. Our study indicates, however, that PD-1 expression, low IFNγ production, and active cycling in TILs are all influenced by IRF4 upregulation after T cell activation.

The purpose of this study was to assess whether cationic nanoliposomes could address tumor vaccines to dendritic cells in the lungs in vivo. Nanoliposomes were prepared using a cationic lipid, dimethylaminoethanecarbamoyl-cholesterol (DC-cholesterol) or dioleoyltrimethylammoniumpropane (DOTAP), and dipalmitoylphosphatidylcholine (DPPC), the most abundant phospholipid in lung surfactant. The liposomes presented a size below 175 nm and they effectively entrapped tumor antigens, an oligodeoxynucletotide containing CpG motifs (CpG) and the fluorescent dye calcein used as a tracer. Although the liposomes could permanently entrap a large fraction of the actives, they could not sustain their release in vitro. Liposomes made of DOTAP were safe to respiratory cells in vitro, while liposomes composed of DC-cholesterol were cytotoxic. DOTAP nanoliposomes were mainly taken up by alveolar macrophages following delivery to the lungs in mice. Few dendritic cells took up the liposomes, and interstitial macrophages did not take up liposomal calcein more than they took up soluble calcein. Stimulation of the innate immune system using liposomal CpG strongly enhanced uptake of calcein liposomes by all phagocytes in the lungs. Although a small percentage of dendritic cells took up the nanoliposomes, alveolar macrophages represented a major barrier to dendritic cell access in the lungs.

Expression of the chemokine receptor Ccr6 is shared by most IL-22–producing cells, and Ccr6-deficient mice showed decreased IL-22 production and skin inflammation upon IL-23 intradermal injections. To determine whether this observation might be extended to another psoriasis model, we applied imiquimod on Ccr6-deficient mice. Although epidermal IL-22 production was decreased because of a deficient recruitment of γδ T cells in these mice, they were not protected against psoriatic lesions. When primary epidermis or dermis tissue culture cells from nontreated mice were stimulated ex vivo with IL-1α/IL-2/IL-23, we observed that Ccr6 is crucial for Il22expression from epidermal but not dermal cultures. Taking advantage of Ccr6-LacZ–knock-in mice, we showed that Ccr6 is necessary for the homing of Ccr6-positive cells, probably a γδ T-cell subset, which represents the main potential IL-22 source in the epidermis. Similar results were observed in Rag1–/–epidermis and dermis primary cultures, in which a subset of innate lymphoid cells expressing Ccr6 represents the main potential source of IL-22. Taken together, our data show that Ccr6 is not required for the development of skin lesions induced by imiquimod despite its effect on epidermal homing of IL-22–producing cells.

The development of therapeutic monoclonal antibodies (mAbs) has revolutionized the treatment of cancer along the last ten years. The best examples of their therapeutic efficacies have been obtained with rituximab for the treatment of CD20 B-cell Non-Hodgkin Lymphoma (B-NHL), and several others antibodies with optimized bioactivities are now being developed for the treatment of various malignant hemopathies. We review here the main drugs developed in this field, and present some emerging concepts able to improve the bioactivities of the next generation of therapeutic mAbs.

Exacerbated IL-22 activity induces tissue inflammation and immune disorders such as psoriasis. However, because IL-22 is also essential for tissue repair and defense at barrier interfaces, targeting IL-22 activity to treat psoriasis bears the risk of deleterious effects at mucosal sites such as the gut. We previously showed in vitro that IL-22 signaling relies on IL-22 receptor alpha Y-dependent and -independent pathways. The second depends on the C-terminal Y-less region of IL-22 receptor alpha and leads to a massive signal transducer and activator of transcription 3 activation. Because signal transducer and activator of transcription 3 activation is associated with the development of psoriasis, we hypothesized that the specific inhibition of the noncanonical signal transducer and activator of transcription 3 activation by the Y-less region of IL-22 receptor alpha could reduce psoriasis-like disease while leaving intact its tissue defense functions in the gut. We show that mice expressing a C-terminally truncated version of IL-22 receptor alpha (ΔCtermut/mutmice) are protected from the development of psoriasis-like dermatitis lesions induced by imiquimod to a lesser extent than Il22ra–/–mice. In contrast, only Il22ra–/–mice lose weight after Citrobacter rodentiuminfection. Altogether, our data suggest that specific targeting of the noncanonical signal transducer and activator of transcription 3 activation by IL-22 could serve to treat psoriasis-like skin inflammation without affecting IL-22‒dependent tissue repair or barrier defense at other sites.

AHR (Récepteur aux aryls hydrocarbures) est un facteur de transcription qui contrôle la production d’IL-22 par différents types cellulaires. Précédemment, nous avons mis en évidence le rôle délétère de l’IL-22 dans un modèle de psoriasis induit par l’application d’imiquimod. Dans cette nouvelle étude, nous avons analysé le rôle de AHR dans ce modèle de psoriasis et sur la production d’IL-22 par les cellules de la peau. Nous montrons que des souris déficientes en AHR sont partiellement protégées contre l’acanthose induite par l’application d’imiquimod au niveau des oreilles et que cette protection est associée à une diminution de l’expression d’IL-22 au niveau de la peau. Nous observons cependant que AHR n’est pas absolument requis pour induire l’expression de l’IL-22. En effet, nous montrons que, au niveau de la peau exposée à l’imiquimod, certains lymphocytes T tels que les lymphocytes T γδ ainsi qu’une population de cellules de l’immunité innée sont toujours capables de produire l’IL-22 en absence de AHR. Si la capacité de ces cellules à produire de l’IL-22 n’est pas affectée par l’absence de AHR, c’est leur recrutement dans la peau enflammée qui est significativement diminué. En conclusion, en absence de AHR, une protection partielle contre le développement d’acanthose en réponse à l’imiquimod est associée à une diminution de l’expression de l’IL-22 qui, elle-même, est secondaire à un défaut de recrutement des cellules productrices de cette cytokine dans la peau.