[Monogenic auto-inflammatory diseases associated with actinopathies: A review of the literature]. / Revue de la littérature sur les syndromes auto-inflammatoires monogéniques liés aux actinopathies.

Auto-inflammatory diseases (AIDs) are diseases resulting from an inappropriate activation of innate immunity in the absence of any infection. The field of monogenic AIDs is constantly expanding, with the discovery of new pathologies and pathophysiological mechanisms thanks to pangenomic sequencing. Actinopathies with auto-inflammatory manifestations are a new emerging group of AIDs, linked to defects in the regulation of the actin cytoskeleton dynamics. These diseases most often begin in the neonatal period and combine to varying degrees a more or less severe primary immune deficiency, cytopenias (especially thrombocytopenia), auto-inflammatory manifestations (especially cutaneous and digestive), atopic and auto-immune manifestations. The diagnosis is to be evoked essentially in front of a cutaneous-digestive auto-inflammation picture of early onset, associated with a primary immune deficiency and thrombocytopenia or a tendency to bleed. Some of these diseases have specificities, including a risk of macrophagic activation syndrome or a tendency to atopy or lymphoproliferation. We propose here a review of the literature on these new diseases, with a proposal for a practical approach according to the main associated biological abnormalities and some clinical particularities. However, the diagnosis remains genetic, and several differential diagnoses must be considered. The pathophysiology of these diseases is not yet fully elucidated, and studies are needed to better clarify the inherent mechanisms that can guide the choice of therapies. In most cases, the severity of the picture indicates allogeneic marrow transplantation.

Exclusion of CD43 from the immunological synapse is mediated by phosphorylation-regulated relocation of the cytoskeletal adaptor moesin.

Formation of the immunological synapse requires TCR signal-dependent protein redistribution. However, the specific molecular mechanisms controlling protein relocation are not well defined. Moesin is a widely expressed phospho-protein that links many transmembrane molecules to the cortical actin cytoskeleton. Here, we demonstrate that TCR-induced exclusion of the large sialoprotein CD43 from the synapse is an active event mediated by its reversible binding to moesin. Our results also reveal that relocalization of moesin is associated with changes in the phosphorylation status of this cytoskeletal adaptor protein. Finally, these findings raise the possibility that the change in moesin localization resulting from TCR engagement modifies the overall topology of the lymphocyte membrane and facilitates molecular interactions at the site of presenting cell contact.

Information transfer at the immunological synapse.

Antigen-specific activation of T lymphocytes requires the interaction of their clonally distributed T-cell receptors with plasma membrane ligands composed of foreign peptide antigens bound to major histocompatibility complex molecules. For proliferation and differentiation to ensue, a variety of other adhesive and accessory proteins must also interact with their counter-receptors on the antigen-presenting cell to facilitate and complement the T-cell receptor-antigen recognition event. Recent studies have revealed that these various proteins show an unexpected degree of spatial organization in the zone of cell-cell contact. This region of membrane approximation is now referred to as the "immunological synapse" because of its functional analogy to the site of intercellular information transfer between neurons. Here, we review the evidence for signaling-dependent control of the dynamic changes in protein distribution that gives rise to the synapse and try to relate the emerging spatio-temporal information on synapse formation to T-cell biology.

Crippling of CD3-zeta ITAMs does not impair T cell receptor signaling.

We evaluated the importance of CD3-zeta ITAMs in T cell responses by breeding the P14 transgenic TCR into mice in which CD3-zeta chains lacking all or part of their ITAMs were genetically substituted for wild-type CD3-zeta chains. In contrast to the H-Y TCR, the P14 TCR permitted the development of peripheral CD8+ T cells harboring signaling-defective CD3-zeta subunits. The absence of functional CD3-zeta ITAMs did not reduce the spectrum of activation events and effector functions that constitute the normal attributes of mature CD8+ T cells. The only detectable differences were quantitative and noted only when T cells were challenged with suboptimal peptide concentrations. Therefore, the ITAMs present in the CD3-gammadeltaepsilon module are sufficient for qualitatively normal TCR signaling and those present in CD3-zeta have no exclusive role during T cell activation.

Chronic intravenous injections of antigen induce and maintain tolerance in T cell receptor-transgenic mice.

Antigen-specific T cell tolerance can be induced by systemic injection of high-dose antigen. In particular, a single intravenous (i.v.) injection of influenza virus hemagglutinin peptide in HNT-TCR transgenic mice induces T cell tolerance through thymocyte apoptosis as well as anergy and deletion of peripheral CD4+ T cells. We now show that this tolerance is reversed after 8 weeks probably due to the short in vivo half-life of the peptide. Since durable tolerance is required for this strategy to be of therapeutic value, we tested whether weekly i.v. injections of peptide (up to 12 weeks) could maintain the CD4+ T cell tolerance. Each injection induces a profound deletion of thymocytes, although their level recovers before the next injection. Therefore, during the treatment period, the thymus undergoes cycles of contraction/expansion. In the periphery, the number of CD4+ T cells is stably decreased and the persisting CD4+ T cells are hyporeactive both in vitro and in vivo. This tolerance is essentially peripheral since comparable results were obtained in thymectomized HNT-TCR mice injected weekly. Our data show that stable antigen-specific tolerance can be induced by repeated i.v. injections of antigen. These findings might have implications for the treatment of T cell-mediated autoimmune diseases.

CD8 expression allows T cell signaling by monomeric peptide-MHC complexes.

Physiologically, TCR signaling is unlikely to result from the cross-linking of TCR-CD3 complexes, given the low density of specific peptide-MHC complexes on antigen-presenting cells. We therefore have tested directly an alternative model for antigen recognition. We show that monomers of soluble peptide-MHC trigger Ca2+ responses in CD8alphabeta+ T cells. This response is not observed in CD8- T cells and when either the CD8:MHC or CD8:Lck interactions are prevented. This demonstrates that an intact CD8 coreceptor is necessary for effective TCR signaling in response to monomeric peptide-MHC molecules. We propose that this heterodimerization of TCR and CD8 by peptide-MHC corresponds to the physiological event normally involved during antigen-specific signal transduction.

Antigen-dependent and -independent Ca2+ responses triggered in T cells by dendritic cells compared with B cells.

Dendritic cells (DCs) are much more potent antigen (Ag)-presenting cells than resting B cells for the activation of naive T cells. The mechanisms underlying this difference have been analyzed under conditions where ex vivo DCs or B cells presented known numbers of specific Ag-major histocompatibility complex (MHC) complexes to naive CD4(+) T cells from T cell antigen receptor (TCR) transgenic mice. Several hundred Ag-MHC complexes presented by B cells were necessary to elicit the formation of a few T-B conjugates with small contact zones, and the resulting individual T cell Ca2+ responses were all-or-none. In contrast, Ag-specific T cell Ca2+ responses can be triggered by DCs bearing an average of 30 Ag-MHC complexes per cell. Formation of T-DC conjugates is Ag-independent, but in the presence of the Ag, the surface of the contact zone increases and so does the amplitude of the T cell Ca2+ responses. These results suggest that Ag is better recognized by T cells on DCs essentially because T-DC adhesion precedes Ag recognition, whereas T-B adhesion requires Ag recognition. Surprisingly, we also recorded small Ca2+ responses in T cells interacting with unpulsed DCs. Using DCs purified from MHC class II knockout mice, we provide evidence that this signal is mostly due to MHC-TCR interactions. Such an Ag-independent, MHC-triggered calcium response could be a survival signal that DCs but not B cells are able to deliver to naive T cells.

Modifications of CD8+ T cell function during in vivo memory or tolerance induction.

Naive monoclonal T cells specific for the male antigen can be stimulated in vivo to eliminate male cells and become memory cells or to permit survival of male cells and become tolerant. Memory cells responded to TCR ligation by cyclic oscillations of calcium levels and immediate secretion of very high levels of IL-2 and interferon-gamma. Tolerant cells did not proliferate in response to ionomycin and phorbol myristate acetate, failing to mobilize calcium to produce IL-2 or express IL-2R, but survived for long time periods in vivo and secreted IL-10. These results emphasize that tolerance is not an absence of all functional activity and may be associated with modifications of behavior conferring important regulatory functions on tolerant T cells.

Imaging antigen recognition by naive CD4+ T cells: compulsory cytoskeletal alterations for the triggering of an intracellular calcium response.

Antigen recognition was analyzed at the single-cell level by using for the first time T cells which were not altered by in vitro selection, transfection or immortalization. The first consequence of antigen recognition by ex vivo naive CD4+ T cells from T cell receptor (TCR)-transgenic mice is the formation of a "contact zone" with the B cell presenting the antigen. The T cell intracellular calcium (Ca2+) response begins after a delay of 30 s on average, following the formation of the contact zone. The T cell response is entirely inhibited by either protein tyrosine kinase or actin polymerization inhibitors but, surprisingly, it is insensitive to inhibitors of phosphoinositide 3-kinase. Moreover, inhibition of microtubule polymerization and use of Ca2+-free medium do not prevent the beginning of the T cell response, but do reduce the stability of the contact zone and/or the amplitude of the Ca2+ plateau. The critical involvement of the cytoskeleton in antigen recognition on B cells introduces a checkpoint in T cell activation: the initial TCR engagement triggers a Ca2+ response only after an amplification step corresponding to a cytoskeleton-controlled increase in the number of engaged TCR.

Reconstituted killer cell inhibitory receptors for major histocompatibility complex class I molecules control mast cell activation induced via immunoreceptor tyrosine-based activation motifs.

Natural killer and T cells express at their surface, members of a multigenic family of killer cell inhibitory receptors (KIR) for major histocompatibility complex Class I molecules. KIR engagement leads to the inhibition of natural killer and T cell activation programs. We investigated here the functional reconstitution of KIR in a non-lymphoid cell type. Using stable transfection in the RBL-2H3 mast cell line, we demonstrated that (i) KIR can inhibit signals induced by FcepsilonRIgamma or CD3zeta polypeptides that bear immunoreceptor tyrosine-based activation motifs; (ii) two distinct immunoreceptor tyrosine-based inhibition motifs-bearing receptors, i.e. KIR and FcgammaRIIB, use distinct inhibitory pathways since KIR engagement inhibits the intracellular Ca2+ release from endoplasmic reticulum stores, in contrast to FcgammaRIIB, which only inhibits extracellular Ca2+ entry; (iii) KIR require co-ligation with an immunoreceptor tyrosine-based activation motif-dependent receptor to mediate their inhibitory function. This latter finding is central to the mechanism by which KIR selectively inhibit only the activatory receptors in close vicinity. Taken together our observations also contribute to define and extend the family of immunoreceptor tyrosine-based inhibition motif-bearing receptors involved in the negative control of cell activation.

The CD8 beta polypeptide is required for the recognition of an altered peptide ligand as an agonist.

T cell activation is triggered by the specific recognition of cognate peptides presented by MHC molecules. Altered peptide ligands are analogs of cognate peptides which have a high affinity for MHC molecules. Some of them induce complete T cell responses, i.e. they act as agonists, whereas others behave as partial agonists or even as antagonists. Here, we analyzed both early (intracellular Ca2+ mobilization), and late (interleukin-2 production) signal transduction events induced by a cognate peptide or a corresponding altered peptide ligand using T cell hybridomas expressing or not the CD8 alpha and beta chains. With a video imaging system, we showed that the intracellular Ca2+ response to an altered peptide ligand induces the appearance of a characteristic sustained intracellular Ca2+ concentration gradient which can be detected shortly after T cell interaction with antigen-presenting cells. We also provide evidence that the same altered peptide ligand can be seen either as an agonist or a partial agonist, depending on the presence of CD8beta in the CD8 co-receptor dimers expressed at the T cell surface.

Effects of nocodazole and taxol on glycine evoked currents on rat spinal cord neurones in culture.

We examined the effect of altering the cytoskeleton polymerization state by treatment with nocodazole and taxol on glycine-evoked currents in patch-clamp recordings from cultured spinal cord neurones. Adding ATP and GTP to the pipette solution did not prevent the rundown of the peak current. In the absence or in the presence of ATP, the proportion of the non-desensitizing part of the glycine evoked-current declined with time. Adding intracellular GTP and ATP stabilized glycine-evoked responses although the proportion of non-inactivating current was reduced. Nocodazole reduced by itself the proportion of the non-inactivating current whereas taxol (with ATP and GTP) had an opposite effect. These results suggest that the polymerization state of microtubules has functional consequences on glycine receptors.