Dissecting the mechanisms responsible for the generation of regulatory versus pathogenic human CD4+ T cells by TLR9-activated plasmacytoid dendritic cells

Abstract Understanding the mechanisms underlying how regulatory and pathogenic CD4+ T cells are generated will accelerate therapeutic target identification in autoimmune diseases such as Systemic Lupus Erythematosus (SLE), where this balance is altered. We recently described that in vitro priming of naïve CD4+ T cells with plasmacytoid DCs (pDCs) activated with either CpGA or Oxidized mitochondrial DNA (Ox mtDNA) leads to the generation of Type 1 regulatory T cells (Tr1) or of a novel T helper subset (Th10 cells), respectively. Th10 cells are expanded in the blood of SLE patients and accumulate within the tubuloinsterstitial areas of proliferative nephritis (PLN) lesions. These cells produce IL10 and mitochondrial ROS (mtROS) as the result of reverse electron transport (RET) fueled by the tricarboxylic acid (TCA) cycle intermediate succinate. Functionally, Th10 cells are not suppressive, but they provide B cell help through the synergistic effect of IL10 and succinate. The mechanisms responsible for the acquisition of a regulatory versus a helper phenotype remain elusive. We now show that naïve CD4+ T cells require the activation of the Delta Like Canonical Notch Ligand 4 (Dll4)-Notch pathway in order to acquire a TH10 phenotype. Conversely, the TLR7-IRF7 pathway is necessary for the generation of Tr1 cells. These pathways might be exploited for therapeutic intervention in human autoimmune diseases.</jats:p

Systemic Lupus Erythematosus Pathogenesis: Interferon and Beyond

Autoreactive B cells and interferons are central players in systemic lupus erythematosus (SLE) pathogenesis. The partial success of drugs targeting these pathways, however, supports heterogeneity in upstream mechanisms contributing to disease pathogenesis. In this review, we focus on recent insights from genetic and immune monitoring studies of patients that are refining our understanding of these basic mechanisms. Among them, novel mutations in genes affecting intrinsic B cell activation or clearance of interferogenic nucleic acids have been described. Mitochondria have emerged as relevant inducers and/or amplifiers of SLE pathogenesis through a variety of mechanisms that include disruption of organelle integrity or compartmentalization, defective metabolism, and failure of quality control measures. These result in extra- or intracellular release of interferogenic nucleic acids as well as in innate and/or adaptive immune cell activation. A variety of classic and novel SLE autoantibody specificities have been found to recapitulate genetic alterations associated with monogenic lupus or to trigger interferogenic amplification loops. Finally, atypical B cells and novel extrafollicular T helper cell subsets have been proposed to contribute to the generation of SLE autoantibodies. Overall, these novel insights provide opportunities to deepen the immunophenotypic surveillance of patients and open the door to patient stratification and personalized, rational approaches to therapy. Expected final online publication date for the Annual Review of Immunology, Volume 41 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates. </jats:p

On/Off TLR Signaling Decides Proinflammatory or Tolerogenic Dendritic Cell Maturation upon CD1d-Mediated Interaction with Invariant NKT Cells

Abstract Invariant NKT (iNKT) cells play an effector/adjuvant function during antimicrobial and antitumoral immunity and a regulatory role to induce immune tolerance and prevent autoimmunity. iNKT cells that differentially modulate adaptive immunity do not bear a unique phenotype and/or specific cytokine secretion profile, thus opening questions on how a single T cell subset can exert opposite immunological tasks. In this study, we show that iNKT cells perform their dual roles through a single mechanism of action relying on the cognate interaction with myeloid dendritic cells (DCs) and leading to opposite effects depending on the presence of other maturation stimuli simultaneously acting on DCs. The contact of murine purified iNKT cells with immature autologous DCs directly triggers the tolerogenic maturation of DCs, rendering them able to induce regulatory T cell differentiation and prevent autoimmune diabetes in vivo. Conversely, the interaction of the same purified iNKT cells with DCs, in the presence of simultaneous TLR4 stimulation, significantly enhances proinflammatory DC maturation and IL-12 secretion. The different iNKT cell effects are mediated through distinct mechanisms and activation of different molecular pathways within the DC: CD1d signaling and activation of the ERK1/2 pathway for the tolerogenic action, and CD40–CD40L interaction and NF-κB activation for the adjuvant effect. Our data suggest that the DC decision to undergo proinflammatory or tolerogenic maturation results from the integration of different signals received at the time of iNKT cell contact and could have important therapeutic implications for exploiting iNKT cell adjuvant/regulatory properties in autoimmune diseases, infections, and cancer.</jats:p

Extracellular vesicle- and particle-mediated communication shapes innate and adaptive immune responses

Intercellular communication among immune cells is vital for the coordination of proper immune responses. Extracellular vesicles and particles (EVPs) act as messengers in intercellular communication, with important consequences for target cell and organ physiology in both health and disease. Under normal physiological conditions, immune cell-derived EVPs participate in immune responses by regulating innate and adaptive immune responses. EVPs play a major role in antigen presentation and immune activation. On the other hand, immune cell-derived EVPs exert immunosuppressive and regulatory effects. Consequently, EVPs may contribute to pathological conditions, such as autoimmune and inflammatory diseases, graft rejection, and cancer progression and metastasis. Here, we provide an overview of the role of EVPs in immune homeostasis and pathophysiology, with a particular focus on their contribution to innate and adaptive immunity and their potential use for immunotherapies.ML