Search

Although tyrosine kinase inhibitor therapy and immunotherapy have significantly improved lung cancer management, many patients do not benefit or become resistant to treatment, highlighting the need for novel treatments. We found elevated CD73 expression to be prevalent in non–small cell lung cancer (NSCLC) including those harboring the RAS- or RTK (EGFR, EML4-ALK) oncogenes. CD73 expression is enriched closely with the transcriptome signature of epithelial–mesenchymal transition and the immune-tolerant tumor microenvironment, which are increasingly relevant for disease progression and therapy resistance. We developed two novel series of CD73 antibody, Ab001/Ab002 and humanized version Hu001/Hu002, which demonstrated high CD73 binding affinity, potent enzyme inhibition, and efficiently protected effector T lymphocyte function from adenosine/cancer-imposed toxicity. Hu001/Hu002 inhibited growth of RAS-mutant NSCLC tumors in mice via enhanced antibody-dependent cell-mediated cytotoxicity and multifaceted remodeling of the tumor immune environment, reflecting diminished levels of tumor-associated macrophages, myeloid-derived suppressor cells, and tumor vasculature. A novel MMAE-conjugated CD73-ADC (Hu001–MMAE) elicited potent cytotoxicity against CD73-high expressing tumor cells (IC50

Amino-acid catabolizing enzymes produced by mononuclear phagocytes play a central role in regulating the immune response. The mammalian phenylalanine-catabolizing enzyme IL4-induced gene 1 (IL4I1) inhibits effector T lymphocyte proliferation and facilitates regulatory T-cell development. IL4I1 expression by macrophages of various human tumors may affect patient prognosis as it facilitates tumor escape from the T-cell response in murine models. Its enzymatic activity appears to participate in its effects, but some actions of IL4I1 remain unclear. Here, we show that the presence of IL4I1 during T-cell activation decreases early signaling events downstream of TCR stimulation, resulting in global T-cell inhibition which is more pronounced when there is CD28 costimulation. Surprisingly, the enzymatic activity of IL4I1 is not involved. Focal secretion of IL4I1 into the immune synaptic cleft and its binding to CD3+ lymphocytes could be important in IL4I1 immunosuppressive mechanism of action. This article is protected by copyright. All rights reserved

Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic approaches used to treat cancer. Immune checkpoint molecules located on tumor cells interact with receptors on cytotoxic CD8+ T cells (a type of effector T lymphocyte) and consequently lead to evasion of tumor cells from the immune system.

Viral infections lead to alarmin release and elicit potent cytotoxic effector T lymphocyte (CTLeff) responses. Conversely, the induction of protective tumour-specific CTLeff and their recruitment into the tumour remain challenging tasks. Here we show that lymphocytic choriomeningitis virus (LCMV) can be engineered to serve as a replication competent, stably-attenuated immunotherapy vector (artLCMV). artLCMV delivers tumour-associated antigens to dendritic cells for efficient CTL priming. Unlike replication-deficient vectors, artLCMV targets also lymphoid tissue stroma cells expressing the alarmin interleukin-33. By triggering interleukin-33 signals, artLCMV elicits CTLeff responses of higher magnitude and functionality than those induced by replication-deficient vectors. Superior anti-tumour efficacy of artLCMV immunotherapy depends on interleukin-33 signalling, and a massive CTLeff influx triggers an inflammatory conversion of the tumour microenvironment. Our observations suggest that replicating viral delivery systems can release alarmins for improved anti-tumour efficacy. These mechanistic insights may outweigh safety concerns around replicating viral vectors in cancer immunotherapy., Viruses trigger potent cytotoxic T cell responses, whereas anti-tumour immunity has been difficult to establish. Here the authors engineer a replicating viral delivery system for tumour-associated antigens, which induces alarmin release, innate activation and protective anti-tumour immunity in mice.

Effector T lymphocytes need to efficiently navigate through complex and diverse microenvironments to reach the site of tissue injury, where they exert their effector functions. To do so, T cells employ a wide range of cell-intrinsically regulated migratory strategies, and negotiate a variety of extracellular biochemical and physical cues for migratory guidance. Recent advances in intravital imaging coupled with new molecular tools have provided novel insights on the cellular and molecular coordination of effector T lymphocyte locomotive behavior in situ . In this article, we detail our current understanding of effector T lymphocyte homing to and migratory behavior within nonlymphoid organs during infection and inflammation and within tumors.

An important regulatory suppressive function in autoimmune and other inflammatory processes has been ascribed to CD4+Foxp3+ regulatory T cells (Tregs), which requires direct cell-cell communication between Tregs, effector T cells, and APCs. However, the molecular basis for these interactions has not yet been clarified. We show here that sialoadhesin (Sn), the prototype of the siglec family of sialic acid-binding transmembrane proteins, expressed by resident and activated tissue-infiltrating macrophages, directly binds to Tregs, negatively regulating their expansion in an animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). In this model, macrophages infiltrate the CNS exhibiting tissue-destructing and demyelinating activity, leading to MS-like symptoms. We show here that severity of EAE symptoms is reduced in Sn knockout (KO) mice compared with wild-type littermates due to an up-regulation of CD4+Foxp3+ Treg lymphocytes. Through the use of a Sn fusion protein, Tregs were shown to express substantial amounts of Sn ligand on their cell surface, and direct interaction of Sn+ macrophages with Tregs specifically inhibited Treg but not effector T lymphocyte proliferation. Conversely, blocking of Sn on macrophages by Sn-specific Abs resulted in elevated proliferation of Tregs. Data indicate that Sn+ macrophages regulate Treg homeostasis which subsequently influences EAE progression. We propose a new direct cell-cell interaction-based mechanism regulating the expansion of the Tregs during the immune response, representing a “dialogue” between Sn+ macrophages and Sn-accessible sialic acid residues on Treg lymphocytes.

Mice deficient in the interferon-gamma (IFN-gamma)-inducible, immunity-related GTPase Irgm1 have defective host resistance to a variety of intracellular pathogens. This greater susceptibility to infection is associated with impaired IFN-gamma-dependent macrophage microbicidal activity in vitro. Here we show that Irgm1 also regulated the survival of mature effector CD4(+) T lymphocytes by protecting them from IFN-gamma-induced autophagic cell death. Mice deficient in both IFN-gamma and Irgm1 were 'rescued' from the lymphocyte depletion and greater mortality that occurs in mice singly deficient in Irgm1 after mycobacterial infection. Our studies identify a feedback mechanism in the T helper type 1 response that limits the detrimental effects of IFN-gamma on effector T lymphocyte survival while promoting the antimicrobial functions of IFN-gamma.

A hallmark of adaptive immunity is the generation of memory T cells that confer long-lived, antigen-specific protection against repeat challenges by pathogens. Understanding the mechanisms by which memory T cells arise is important for rational vaccination strategies and improved therapeutic interventions for chronic infections and autoimmune disorders. The large clonal expansion of CD8 T cells in response to some infections has made the development of CD8 T-cell memory more amenable to study, giving rise to a model of memory cell differentiation in which a fraction of fully competent effector T cells transition into long-lived memory T cells. Delineation of CD4 T-cell memory development has proved more difficult as a result of limitations on tracking the smaller populations of CD4 effector T cells generated during a pathogenic challenge, complicating efforts to determine whether CD4 memory T cells are direct descendants of effector T cells or whether they develop by alternative pathways. Here, using two complementary cytokine reporter mouse models to identify interferon (IFN)-gamma-positive effector T cells and track their fate, we show that the lineage relationship between effector and memory CD4 T cells resembles that for CD8 T cells responding to the same pathogen. We find that, in parallel with effector CD8 T cells, IFN-gamma-positive effector CD4 T cells give rise to long-lived memory T cells capable of anamnestic responses to antigenic rechallenge.

Leukotriene B4 is a lipid mediator that recently has been shown to have potent chemotactic activity for effector T lymphocytes mediated through its receptor, BLT1. Here, we developed a novel murine model of acute lung rejection to demonstrate that BLT1 controls effector CD8+ T cell trafficking into the lung and that disruption of BLT1 signaling in CD8+ T cells reduces lung inflammation and mortality in the model. In addition, we used BLT1-deficient mice and a BLT1 antagonist in two tracheal transplant models of lung transplantation to demonstrate the importance of BLT1 for the recruitment of T cells into tracheal allografts. We also show that BLT1-mediated CD8+ T cell recruitment plays an important role in the development of airway fibroproliferation and obliteration. Finally, in human studies of lung transplant recipients, we found that BLT1 is up-regulated on T lymphocytes isolated from the airways of patients with obliterative bronchiolitis. These data demonstrate that BLT1 contributes to the development of lung rejection and obliterative bronchiolitis by mediating effector T lymphocyte trafficking into the lung. This is the first report that describes a pathologic role for BLT1-mediated T lymphocyte recruitment in disease and identifies BLT1 as a potential therapeutic target after lung transplantation.

The landmark discovery of pattern-recognition receptors, including Toll-like receptors (TLRs), furthered our understanding on how the host rapidly responds to invading pathogens. For over a decade now, extensive research has demonstrated the crucial role of multiple TLRs in the detection of a broad range of molecules expressed by microbial pathogens as well as host-derived danger signals. TLR activation is the hallmark of the innate immune response. Recent evidence, however, demonstrates that cells of the adaptive immune response use these innate signaling pathways as well. This review discusses recent findings regarding TLR functionality in T lymphocytes with a specific emphasis on the promotion of T helper cell-dependent inflammation through direct TLR signaling.

Fibrotic autoimmune diseases are characterized by an inflammatory process in which fibrogenic cytokines, such as TGFβ and IL6, have a major role. Interestingly, these cytokines are also involved in the generation and function of both an effector T lymphocyte subpopulation, the Th17 cells, and the regulatory T lymphocytes (Treg). These evidences raised the hypothesis that an unbalanced equilibrium induced by the overproduction of the fibrogenic cytokines may have pathogenic relevance in fibrotic autoimmune diseases. On this basis, this review analyzes the available data concerning Th17 and Treg generation and function in two representative fibrotic autoimmune diseases, primary biliary cirrhosis (PBC) and systemic sclerosis (SSc), as models for organ-specific and systemic diseases, respectively. With regard to the Th17 cells, their expansion was found to be a common feature associated with a relative contraction of Th1 immune responses. Concerning to the regulatory T cell compartment, quantitative and qualitative alterations were observed in both diseases. However, while PBC patients showed defects only in the CD8 + Treg subset, SSc patients demonstrated abnormalities regarding to both the CD4 + CD25 + and the CD8 + Treg subpopulations. Hence, the CD8 + Treg subset seems to be the most involved in the pathogenic cascade leading to fibrotic disease onset and maintenance. Collectively, the reviewed data support the concept that altered homeostasis between effector and regulatory T cell circuits is present in fibrotic autoimmune diseases and that the major factors responsible for such disequilibrium are Th17 cells in the effector arm and CD8 + Treg in the regulatory arm. © 2012 Elsevier B.V

Summary Control of Mycobacterium tuberculosis ( M. tuberculosis ) infection is dependent on recognition of bacilli by cells of the innate immune system in the lung and the subsequent generation of an acquired effector T lymphocyte response. Lipid moieties of M. tuberculosis are important stimulators of innate immunity mediated predominantly through recognition by Toll-like receptors. In this paper, we will discuss how the lipid composition of different clinical isolates (strains) of M. tuberculosis affect that strain's ability to direct innate immunity, and ultimately influence whether infection is controlled or active disease develops.

Background Recent genome-wide association studies (GWAS) have revealed numerous genetic associations between specific single-nucleotide polymorphisms (SNPs) and spondyloarthritis (SpA), a highly heritable arthropathy. These studies highlighted the importance of non-HLA genes, in particular of key components of the IL-23 signaling pathway such as IL23R and IL12B, as well as genes associated with other pathways such as ERAP1 and ANTXR2. However, the link between these genes and the disease mechanisms remained unknown. Objectives The current challenge is to define associations between defined genetic variants and effector mechanisms implicated in disease pathogenesis. Here, we have investigated the link between genetic variants associated with spondyloarthritis (SpA) and the function of CD4+ effector T lymphocyte subsets, known mediators of chronic inflammatory disease. Methods To assess if genetic variants at IL23R and other genes in the IL-23/IL-17 pathway affect CD4+ T cell functions, we isolated CD4+ T cells from the peripheral blood of 49 SpA patients and stimulated them through the T cell receptor in vitro. We then analyzed the expression of genes associated with development and function of Th1 and Th17 cells. Genotyping was performed using pre-developed TaqMan allelic discrimination assays and immunophenotyping using standard flow cytometry panels. Results We found that selected disease-associated polymorphisms in genes involved in the IL-23 signaling pathway, such as IL23R, IL12B and CCR6, correlated with the expression levels of genes controlling differentiation and function of inflammatory Th1 and Th17 cells in SpA patients. In contrast, genetic variation at loci genetically linked to SpA, but not associated with the IL-23 pathway, had no measurable impact on the expression of inflammatory cytokines. To assess the global effect of multiple SNPs on CD4 effector functions, we correlated the numbers of susceptibility or protective alleles at molecules in the IL-23 pathway that each patient carried with the expression levels of Th1 and Th17 cytokine genes. Patients carrying predominantly alleles associated with increased disease risk expressed overall higher levels of effector cytokines. In contrast, patients carrying the highest number of protective alleles expressed the lowest levels of these cytokine genes. Conclusions Our data revealed a combinatorial control of T helper cell effector functions by SNPs at genes associated with the IL-23 signaling pathway in SpA patients and provide a framework to delineate the mechanisms by which genetic variants may contribute to SpA pathogenesis. We propose that genetic variation at genes in the IL-23/IL-17 axis tunes the homeostasis of CD4 effector cell populations, by affecting the frequencies of inflammatory T cell subsets. Disclosure of Interest None Declared

The thymus gland has been known for some time to be the central organ of differentiation of T lymphocytes1,2. Stem cells migrate into the thymus from the bone marrow, differentiate and, as competent T lymphocytes, disperse from the thymus to the periphery, where contact with specific antigen induces immune reactivity2. The traffic of T lymphocytes between the thymus and periphery has been thought to be unidirectional and, unless the cells are leukaemic3 or the thymus gland has been irradiated4, re-entry of peripheral T lymphocytes has not been detected3. We now report that cells from lines of functionally active T lymphocytes reactive to self or foreign antigens can migrate back into the normal thymus gland and persist there for relatively long periods in a quiescent state until activated by contact with antigen. Hence, in addition to being the seat of T lymphocyte differentiation, the thymus is open to two-way traffic with the periphery and may function as a repository of immunological memory.