The Impact of Ly49-NK Cell-Dependent Recognition of MCMV Infection on Innate and Adaptive Immune Responses

Clinical and experimental data indicate that a subset of innate lymphocytes, natural killer (NK) cells, plays a crucial role in the response against herpesviruses, especially cytomegaloviruses (CMV). Indeed, in mice, NK cells, due to the expression of germline encoded Ly49 receptors, possess multiple mechanisms to recognize CMV infection. Classically, this results in NK cell activation and the destruction of the infected cells. More recently, however, this unique host-pathogen interaction has permitted the discovery of novel aspects of NK cell biology, implicating them in the regulation of adaptive immune responses as well as in the development of immunological memory. Here, we will concisely review the newly acquired evidence pertaining to NK cell Ly49-dependent recognition of MCMV-infected cell and the ensuing NK cell regulatory responses

CEACAM1 regulates TIM-3-mediated tolerance and exhaustion

T-cell immunoglobulin domain and mucin domain-3 (TIM-3, also known as HAVCR2) is an activation-induced inhibitory molecule involved in tolerance and shown to induce T-cell exhaustion in chronic viral infection and cancers[superscript 1, 2, 3, 4, 5]. Under some conditions, TIM-3 expression has also been shown to be stimulatory. Considering that TIM-3, like cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), is being targeted for cancer immunotherapy, it is important to identify the circumstances under which TIM-3 can inhibit and activate T-cell responses. Here we show that TIM-3 is co-expressed and forms a heterodimer with carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), another well-known molecule expressed on activated T cells and involved in T-cell inhibition[superscript 6, 7, 8, 9, 10]. Biochemical, biophysical and X-ray crystallography studies show that the membrane-distal immunoglobulin-variable (IgV)-like amino-terminal domain of each is crucial to these interactions. The presence of CEACAM1 endows TIM-3 with inhibitory function. CEACAM1 facilitates the maturation and cell surface expression of TIM-3 by forming a heterodimeric interaction in cis through the highly related membrane-distal N-terminal domains of each molecule. CEACAM1 and TIM-3 also bind in trans through their N-terminal domains. Both cis and trans interactions between CEACAM1 and TIM-3 determine the tolerance-inducing function of TIM-3. In a mouse adoptive transfer colitis model, CEACAM1-deficient T cells are hyper-inflammatory with reduced cell surface expression of TIM-3 and regulatory cytokines, and this is restored by T-cell-specific CEACAM1 expression. During chronic viral infection and in a tumour environment, CEACAM1 and TIM-3 mark exhausted T cells. Co-blockade of CEACAM1 and TIM-3 leads to enhancement of anti-tumour immune responses with improved elimination of tumours in mouse colorectal cancer models. Thus, CEACAM1 serves as a heterophilic ligand for TIM-3 that is required for its ability to mediate T-cell inhibition, and this interaction has a crucial role in regulating autoimmunity and anti-tumour immunity.American Association for Cancer Research. Pancreatic Cancer Action Networ

Ly49P recognition of cytomegalovirus-infected cells expressing H2-Dk and CMV-encoded m04 correlates with the NK cell antiviral response

Natural killer (NK) cells are crucial in resistance to certain viral infections, but the mechanisms used to recognize infected cells remain largely unknown. Here, we show that the activating Ly49P receptor recognizes cells infected with mouse cytomegalovirus (MCMV) by a process that requires the presence of H2-Dk and the MCMV m04 protein. Using H2 chimeras between H2-Db and -Dk, we demonstrate that the H2-Dk peptide-binding platform is required for Ly49P recognition. We identified m04 as a viral component necessary for recognition using a panel of MCMV-deletion mutant viruses and complementation of m04-deletion mutant (Δm04) virus infection. MA/My mice, which express Ly49P and H2-Dk, are resistant to MCMV; however, infection with Δm04 MCMV abrogates resistance. Depletion of NK cells in MA/My mice abrogates their resistance to wild-type MCMV infection, but does not significantly affect viral titers in mice infected with Δm04 virus, implicating NK cells in host protection through m04-dependent recognition. These findings reveal a novel mechanism of major histocompatability complex class I–restricted recognition of virally infected cells by an activating NK cell receptor

Cytomegalovirus immunoevasin reveals the physiological role of “missing self” recognition in natural killer cell dependent virus control in vivo

Natural killer cell recognition of “missing self” contributes meaningfully to control of mouse cytomegalovirus infection in vivo

TGF-[beta]1 selectively induces Foxp3 transcription factor and regulatory functions in CD4+CD25⁻CD45RBLow T cell population

CD4+ regulatory T (TREG) cells are important contributors to the induction and maintenance of peripheral tolerance. This heterogeneous population consists of naturally occurring and induced CD4 + TREG cells that share between themselves key immunoregulatory characteristics. Their phenotype and function often relies on the expression of Foxp3 transcription factor and the presence of the immunomodulating cytokine TGF-beta1. The inter-dependence between TGF-beta1 and Foxp3 in the induction and maintenance of peripheral tolerance is gradually being elucidated. Thus, we investigated the effects of TGF-beta1 on induction or maintenance of regulatory functions in CD4+CD25- as well as CD4+CD25+ T cells. TGF-beta1 treatment was able, independent from APCs, to promote TREG cell differentiation from non-regulatory CD4+CD25- T cells in a concentration-dependent fashion through Foxp3 induction. Next, we investigated the effect of TGF-beta1 on purely naive CD4+CD25- CD45RBHIGH T cell subset. Fresh or TGF-beta1-treated CD45RBHIGH T cells did not display regulatory functions nor Foxp3 expression. In stark contrast, TGF-beta1 treatment promoted regulatory activity in the CD4 +CD25- CD45RBLOW T cells and enhanced Foxp3 expression. Interestingly, fresh CD45RBLOW cells, albeit expressing noticeable levels of Foxp3 mRNA and protein, were unable to suppress effector T (TEFF) cell proliferation. Furthermore, addition of neutralizing anti-IL-10R Ab completely abrogated this suppression, consistent with the ability of TGF-beta1 treated CD45RBLOW to synthesize IL-10 mRNA upon re-stimulation in vitro. TGF-beta1 treatment or blockade did not lead to preferential growth or enhanced function of naturally-occurring CD4+CD25+ TREG cells, yet it caused a significant increase in Foxp3 expression. Altogether, TGF-beta1 preferentially promotes the induction of IL-10 secreting CD4+ regulatory T cells from CD45RBLOW precursors through Foxp3 induction

Immunogenetics of infection: MHC class I molecules and NK cell receptors interplay in the recognition of MCMV-infected cell and infection outcome

Human cytomegalovirus (HCMV) is a herpesvirus found commonly in the world population, causing a severe and potentially fatal disease in neonates and immunocompromised patients. Clinical and experimental data indicate that a subset of innate lymphocytes, natural killer (NK) cells, plays a crucial role in resistance to infection. As infection with mouse CMV (MCMV) shares many pathophysiological aspects with the human disease, the mouse represents an excellent model to study CMV infection. The outcome of MCMV infection depends on the host genetic background and thus varies among the multiple inbred mouse strains. Importantly, mouse NK cells, through the expression of germ line encoded receptors, have the ability to recognize CMV infection, resulting in NK cell activation and the destruction of the infected cells. In each strain NK cells express amongst others, different sets of activating and inhibitory Ly49 receptors, in the presence of strain-specific MHC class I molecules, some of which are natural ligands to Ly49 receptors. Nevertheless, the exact mode of NK cell recognition of infected cell and the impact on the outcome of infection are complex and not fully understood. In order to characterize the molecular mechanisms underlying innate resistance to MCMV, we have initiated a systematic study to identify the possible ligands of Ly49 receptors and the nature of their interaction. We assessed the ability of distinct activating and inhibitory Ly49 receptors to recognize MCMV infection, in the context of diverse MHC class I haplotypes in vitro and in vivo. We show that the cognate interaction between several activating Ly49 receptors and MHC class I molecules depends on the presence of the viral regulator of antigen presentation, gp34/m04. Furthermore, we illustrate that, analogous to activating Ly49 receptors, inhibitory Ly49 receptors can be triggered by MCMV infection. This complex interaction, conditional on the type of MHC class I molecules, results in a spectrum of innate immune control of MCMV spread. Altogether, our results identify the fundamental mechanisms of NK cell receptor function in the recognition and eradication of viral infection. These will provide new grounds to understand and manipulate human NK cells in response to viral infections.Le cytomégalovirus humain (HCMV) est un herpèsvirus omniprésent dans la population mondiale, qui provoque des symptômes graves et potentiellement mortels chez les nouveau-nés et les patients immunodéprimés. Les données cliniques et expérimentales indiquent qu'un sous-ensemble de lymphocytes innés, dites tueuses naturelles (NK), joue un rôle crucial dans la résistance à l'infection. Comme l'infection par le CMV murin (MCMV) partage de nombreux aspects physiopathologiques de la maladie humaine, la souris constitue un excellent modèle pour étudier l'infection par le CMV. La susceptibilité au MCMV varie grandement selon les lignées de souris congéniques et ce, en fonction de leur patrimoine génétique. Plus précisément, chaque lignée de souris exprime une variété de récepteurs activateurs ou inhibiteurs spécifiques aux cellules NK, les récepteurs Ly49, parallèlement à des répertoires de CMH de classe I variés, dont certains sont des ligands naturels des récepteurs Ly49. En effet, les cellules NK, grâce à l'expression de ces récepteurs encodés dans la lignée germinale, ont la capacité de reconnaître une infection au CMV, ce qui entraîne leur activation et la destruction des cellules infectées. Néanmoins, le mode exact de reconnaissance des cellules infectées par les cellules NK et l'impact sur l'issue de l'infection sont complexes et encore mal compris. Afin de caractériser les mécanismes moléculaires qui sous-tendent la résistance innée au MCMV, nous avons entrepris une étude systématique des ligands possibles des récepteurs Ly49 et de la nature de leur interaction. Nous avons évalué la capacité de reconnaître l'infection MCMV de différents récepteurs Ly49 activateurs ou inhibiteurs, dans le contexte de divers haplotypes de CMH de classe I in vitro et in vivo. Nous démontrons que l'interaction spécifique entre plusieurs récepteurs Ly49 activateurs et des molécules du CMH de classe I dépend de la présence de gp34/m04, un régulateur viral de la présentation d'antigène. De plus, nous montrons que, comme les récepteurs Ly49 activateurs, les récepteurs Ly49 inhibiteurs peuvent aussi être stimulés par une infection au MCMV. Cette interaction complexe, qui dépend du type de molécules de CMH de classe I, se traduit par des niveaux variable de contrôle de la propagation du MCMV par le système immunitaire. Nos résultats mettent en évidence des mécanismes fondamentaux de la fonction des récepteurs des cellules NK dans la reconnaissance et l'éradication de l'infection virale, et fournissent de nouvelles avenues pour comprendre et manipuler la réponse des cellules NK humaines aux infections virales

Neonatal Fc receptors for IgG drive CD8+ T cell-mediated anti-cancer immunosurveillance at tolerogenic mucosal sites

Mucosal boundaries, which are immunologically tolerogenic, and is further enhanced by undergo malignant transformation at high rates. We have identified the expression of neonatal Fc receptor for IgG (FcRn) by dendritic cells as a critical mediator of mucosal anti-cancer immunosurveillance. This discovery extends our understanding of neonatal Fc receptors, defines a role for tumor-reactive IgGs, and identifies an avenue for the development of novel anti-cancer therapeutics

Tolerogenic properties of the Fc portion of IgG and its relevance to the treatment and management of hemophilia

International audienc