RESUMO
Regionalized immune surveillance relies on the concerted efforts of diverse memory T cell populations. Of these, tissue-resident memory T (TRM) cells are strategically positioned in barrier tissues, where they enable efficient frontline defense against infections and cancer. However, the long-term persistence of these cells has been implicated in a variety of immune-mediated pathologies. Consequently, modulating TRM cell populations represents an attractive strategy for novel vaccination and therapeutic interventions against tissue-based diseases. Here, we provide an updated overview of TRM cell heterogeneity and function across tissues and disease states. We discuss mechanisms of TRM cell-mediated immune protection and their potential contributions to autoimmune disorders. Finally, we examine how TRM cell responses might be durably boosted or dampened for therapeutic gain.
Assuntos
Memória Imunológica , Células T de Memória , Humanos , Animais , Células T de Memória/imunologia , Células T de Memória/metabolismo , Doenças Autoimunes/imunologia , Doenças Autoimunes/terapia , Especificidade de Órgãos/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Vigilância ImunológicaRESUMO
Lymphocytes spanning the entire innate-adaptive spectrum can stably reside in tissues and constitute an integral component of the local defense network against immunological challenges. In tight interactions with the epithelium and endothelium, tissue-resident lymphocytes sense antigens and alarmins elicited by infectious microbes and abiotic stresses at barrier sites and mount effector responses to restore tissue homeostasis. Of note, such a host cell-directed immune defense system has been recently demonstrated to surveil epithelial cell transformation and carcinoma development, as well as cancer cell metastasis at selected distant organs, and thus represents a primordial cancer immune defense module. Here we review how distinct lineages of tissue-resident innate lymphoid cells, innate-like T cells, and adaptive T cells participate in a form of multilayered cancer immunity in murine models and patients, and how their convergent effector programs may be targeted through both shared and private regulatory pathways for cancer immunotherapy.
Assuntos
Imunidade Inata , Neoplasias , Humanos , Animais , Neoplasias/imunologia , Neoplasias/terapia , Linfócitos/imunologia , Linfócitos/metabolismo , Microambiente Tumoral/imunologia , Imunidade Adaptativa , Imunoterapia/métodosRESUMO
The liver's unique characteristics have a profound impact on the priming and maintenance of adaptive immunity. This review delves into the cellular circuits that regulate adaptive immune responses in the liver, with a specific focus on hepatitis B virus infection as an illustrative example. A key aspect highlighted is the liver's specialized role in priming CD8+ T cells, leading to a distinct state of immune hyporesponsiveness. Additionally, the influence of the liver's hemodynamics and anatomical features, particularly during liver fibrosis and cirrhosis, on the differentiation and function of adaptive immune cells is discussed. While the primary emphasis is on CD8+ T cells, recent findings regarding the involvement of B cells and CD4+ T cells in hepatic immunity are also reviewed. Furthermore, we address the challenges ahead and propose integrating cutting-edge techniques, such as spatial biology, and combining mouse models with human sample analyses to gain comprehensive insights into the liver's adaptive immunity. This understanding could pave the way for novel therapeutic strategies targeting infectious diseases, malignancies, and inflammatory liver conditions like metabolic dysfunction-associated steatohepatitis and autoimmune hepatitis.
Assuntos
Imunidade Adaptativa , Fígado , Humanos , Animais , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Linfócitos T CD8-Positivos/imunologia , Vírus da Hepatite B/imunologia , Vírus da Hepatite B/fisiologia , Hepatite B/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos T CD4-Positivos/imunologiaRESUMO
Many of the pathways that underlie the diversification of naive T cells into effector and memory subsets, and the maintenance of these populations, remain controversial. In recent years a variety of experimental tools have been developed that allow us to follow the fates of cells and their descendants. In this review we describe how mathematical models provide a natural language for describing the growth, loss, and differentiation of cell populations. By encoding mechanistic descriptions of cell behavior, models can help us interpret these new datasets and reveal the rules underpinning T cell fate decisions, both at steady state and during immune responses.
Assuntos
Memória Imunológica , Linfócitos T , Humanos , Animais , Diferenciação Celular , Subpopulações de Linfócitos T , Linfócitos T CD8-PositivosRESUMO
T cells and natural killer (NK) cells have complementary roles in tumor immunity, and dual T cell and NK cell attack thus offers opportunities to deepen the impact of immunotherapy. Recent work has also shown that NK cells play an important role in recruiting dendritic cells to tumors and thus enhance induction of CD8 T cell responses, while IL-2 secreted by T cells activates NK cells. Targeting of immune evasion mechanisms from the activating NKG2D receptor and its MICA and MICB ligands on tumor cells offers opportunities for therapeutic intervention. Interestingly, T cells and NK cells share several important inhibitory and activating receptors that can be targeted to enhance T cell- and NK cell-mediated immunity. These inhibitory receptor-ligand systems include CD161-CLEC2D, TIGIT-CD155, and NKG2A/CD94-HLA-E. We also discuss emerging therapeutic strategies based on inhibitory and activating cytokines that profoundly impact the function of both lymphocyte populations within tumors.
Assuntos
Células Matadoras Naturais , Neoplasias , Humanos , Animais , Antígenos de Histocompatibilidade Classe I , Linfócitos T CD8-Positivos , Imunoterapia , Imunidade CelularRESUMO
Transforming growth factor ß (TGF-ß) is a key cytokine regulating the development, activation, proliferation, differentiation, and death of T cells. In CD4+ T cells, TGF-ß maintains the quiescence and controls the activation of naive T cells. While inhibiting the differentiation and function of Th1 and Th2 cells, TGF-ß promotes the differentiation of Th17 and Th9 cells. TGF-ß is required for the induction of Foxp3 in naive T cells and the development of regulatory T cells. TGF-ß is crucial in the differentiation of tissue-resident memory CD8+ T cells and their retention in the tissue, whereas it suppresses effector T cell function. In addition, TGF-ß also regulates the generation or function of natural killer T cells, γδ T cells, innate lymphoid cells, and gut intraepithelial lymphocytes. Here I highlight the major findings and recent advances in our understanding of TGF-ß regulation of T cells and provide a personal perspective of the field.
Assuntos
Linfócitos T CD8-Positivos , Fator de Crescimento Transformador beta1 , Animais , Humanos , Diferenciação Celular , Imunidade Inata , Linfócitos/metabolismo , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta1/metabolismoRESUMO
A high diversity of αß T cell receptors (TCRs), capable of recognizing virtually any pathogen but also self-antigens, is generated during T cell development in the thymus. Nevertheless, a strict developmental program supports the selection of a self-tolerant T cell repertoire capable of responding to foreign antigens. The steps of T cell selection are controlled by cortical and medullary stromal niches, mainly composed of thymic epithelial cells and dendritic cells. The integration of important cues provided by these specialized niches, including (a) the TCR signal strength induced by the recognition of self-peptide-MHC complexes, (b) costimulatory signals, and (c) cytokine signals, critically controls T cell repertoire selection. This review discusses our current understanding of the signals that coordinate positive selection, negative selection, and agonist selection of Foxp3+ regulatory T cells. It also highlights recent advances that have unraveled the functional diversity of thymic antigen-presenting cell subsets implicated in T cell selection.
Assuntos
Sinais (Psicologia) , Receptores de Antígenos de Linfócitos T , Animais , Humanos , Ativação Linfocitária , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais , Linfócitos T ReguladoresRESUMO
The immune system employs recognition tools to communicate with its microbial evolutionary partner. Among all the methods of microbial perception, T cells enable the widest spectrum of microbial recognition resolution, ranging from the crudest detection of whole groups of microbes to the finest detection of specific antigens. The application of this recognition capability to the crucial task of combatting infections has been the focus of classical immunology. We now appreciate that the coevolution of the immune system and the microbiota has led to development of a lush immunological decision tree downstream of microbial recognition, of which an inflammatory response is but one branch. In this review we discuss known T cell-microbe interactions in the gut and place them in the context of an algorithmic framework of recognition, context-dependent interpretation, and response circuits across multiple levels of microbial recognition resolution. The malleability of T cells in response to the microbiota presents an opportunity to edit immune response cellularity, identity, and functionality by utilizing microbiota-controlled pathways to promote human health.
Assuntos
Microbiota , Linfócitos T , Animais , HumanosRESUMO
Throughout the body, T cells monitor MHC-bound ligands expressed on the surface of essentially all cell types. MHC ligands that trigger a T cell immune response are referred to as T cell epitopes. Identifying such epitopes enables tracking, phenotyping, and stimulating T cells involved in immune responses in infectious disease, allergy, autoimmunity, transplantation, and cancer. The specific T cell epitopes recognized in an individual are determined by genetic factors such as the MHC molecules the individual expresses, in parallel to the individual's environmental exposure history. The complexity and importance of T cell epitope mapping have motivated the development of computational approaches that predict what T cell epitopes are likely to be recognized in a given individual or in a broader population. Such predictions guide experimental epitope mapping studies and enable computational analysis of the immunogenic potential of a given protein sequence region.
Assuntos
Epitopos de Linfócito T/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Biomarcadores , Biologia Computacional/métodos , Suscetibilidade a Doenças , Antígenos de Histocompatibilidade/imunologia , Humanos , Ligantes , Aprendizado de Máquina , Ligação ProteicaRESUMO
Neuroimmunology, albeit a relatively established discipline, has recently sparked numerous exciting findings on microglia, the resident macrophages of the central nervous system (CNS). This review addresses meningeal immunity, a less-studied aspect of neuroimmune interactions. The meninges, a triple layer of membranes-the pia mater, arachnoid mater, and dura mater-surround the CNS, encompassing the cerebrospinal fluid produced by the choroid plexus epithelium. Unlike the adjacent brain parenchyma, the meninges contain a wide repertoire of immune cells. These constitute meningeal immunity, which is primarily concerned with immune surveillance of the CNS, and-according to recent evidence-also participates in postinjury CNS recovery, chronic neurodegenerative conditions, and even higher brain function. Meningeal immunity has recently come under the spotlight owing to the characterization of meningeal lymphatic vessels draining the CNS. Here, we review the current state of our understanding of meningeal immunity and its effects on healthy and diseased brains.
Assuntos
Sistema Nervoso Central/imunologia , Sistema Nervoso Central/metabolismo , Suscetibilidade a Doenças , Homeostase , Imunidade , Meninges/fisiologia , Animais , Humanos , Vasos Linfáticos/imunologia , Vasos Linfáticos/metabolismo , Neuroimunomodulação , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Neonatal CD4+ and CD8+ T cells have historically been characterized as immature or defective. However, recent studies prompt a reinterpretation of the functions of neonatal T cells. Rather than a population of cells always falling short of expectations set by their adult counterparts, neonatal T cells are gaining recognition as a distinct population of lymphocytes well suited for the rapidly changing environment in early life. In this review, I will highlight new evidence indicating that neonatal T cells are not inert or less potent versions of adult T cells but instead are a broadly reactive layer of T cells poised to quickly develop into regulatory or effector cells, depending on the needs of the host. In this way, neonatal T cells are well adapted to provide fast-acting immune protection against foreign pathogens, while also sustaining tolerance to self-antigens.
Assuntos
Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Imunidade Adaptativa , Animais , Biomarcadores , Diferenciação Celular/imunologia , Interações Hospedeiro-Patógeno , Humanos , Memória Imunológica , Ativação Linfocitária/imunologia , Células Progenitoras Linfoides/citologia , Células Progenitoras Linfoides/imunologia , Células Progenitoras Linfoides/metabolismo , Fenótipo , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/citologiaRESUMO
Naturally occurring CD4+ regulatory T cells (Tregs), which specifically express the transcription factor FoxP3 in the nucleus and CD25 and CTLA-4 on the cell surface, are a functionally distinct T cell subpopulation actively engaged in the maintenance of immunological self-tolerance and homeostasis. Recent studies have facilitated our understanding of the cellular and molecular basis of their generation, function, phenotypic and functional stability, and adaptability. It is under investigation in humans how functional or numerical Treg anomalies, whether genetically determined or environmentally induced, contribute to immunological diseases such as autoimmune diseases. Also being addressed is how Tregs can be targeted to control physiological and pathological immune responses, for example, by depleting them to enhance tumor immunity or by expanding them to treat immunological diseases. This review discusses our current understanding of Treg immunobiology in normal and disease states, with a perspective on the realization of Treg-targeting therapies in the clinic.
Assuntos
Suscetibilidade a Doenças , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Doenças Autoimunes/terapia , Autoimunidade , Biomarcadores , Gerenciamento Clínico , Humanos , Ativação Linfocitária/imunologia , Terapia de Alvo Molecular , Tolerância a Antígenos Próprios/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
Foxp3-expressing CD4+ regulatory T (Treg) cells play key roles in the prevention of autoimmunity and the maintenance of immune homeostasis and represent a major barrier to the induction of robust antitumor immune responses. Thus, a clear understanding of the mechanisms coordinating Treg cell differentiation is crucial for understanding numerous facets of health and disease and for developing approaches to modulate Treg cells for clinical benefit. Here, we discuss current knowledge of the signals that coordinate Treg cell development, the antigen-presenting cell types that direct Treg cell selection, and the nature of endogenous Treg cell ligands, focusing on evidence from studies in mice. We also highlight recent advances in this area and identify key unanswered questions.
Assuntos
Diferenciação Celular/imunologia , Linfopoese/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Animais , Apresentação de Antígeno/imunologia , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Biomarcadores , Diferenciação Celular/genética , Deleção Clonal , Seleção Clonal Mediada por Antígeno , Humanos , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Linfopoese/genética , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/citologia , Timo/citologia , Timo/imunologia , Timo/metabolismoRESUMO
Malignant transformation of cells depends on accumulation of DNA damage. Over the past years we have learned that the T cell-based immune system frequently responds to the neoantigens that arise as a consequence of this DNA damage. Furthermore, recognition of neoantigens appears an important driver of the clinical activity of both T cell checkpoint blockade and adoptive T cell therapy as cancer immunotherapies. Here we review the evidence for the relevance of cancer neoantigens in tumor control and the biological properties of these antigens. We discuss recent technological advances utilized to identify neoantigens, and the T cells that recognize them, in individual patients. Finally, we discuss strategies that can be employed to exploit cancer neoantigens in clinical interventions.
Assuntos
Antígenos de Neoplasias/imunologia , Autoantígenos/imunologia , Vacinas Anticâncer/imunologia , Epitopos de Linfócito T/imunologia , Imunoterapia Adotiva/métodos , Neoplasias/imunologia , Linfócitos T/imunologia , Animais , Antígenos de Neoplasias/genética , Autoantígenos/genética , Epitopos de Linfócito T/genética , Humanos , Imunidade Celular , Ativação Linfocitária , Medicina de Precisão , Linfócitos T/transplanteRESUMO
The intestinal microbiota plays a crucial role in influencing the development of host immunity, and in turn the immune system also acts to regulate the microbiota through intestinal barrier maintenance and immune exclusion. Normally, these interactions are homeostatic, tightly controlled, and organized by both innate and adaptive immune responses. However, a combination of environmental exposures and genetic defects can result in a break in tolerance and intestinal homeostasis. The outcomes of these interactions at the mucosal interface have broad, systemic effects on host immunity and the development of chronic inflammatory or autoimmune disease. The underlying mechanisms and pathways the microbiota can utilize to regulate these diseases are just starting to emerge. Here, we discuss the recent evidence in this area describing the impact of microbiota-immune interactions during inflammation and autoimmunity, with a focus on barrier function and CD4+ T cell regulation.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Diabetes Mellitus Tipo 1/microbiologia , Microbioma Gastrointestinal/imunologia , Inflamação/microbiologia , Doenças Inflamatórias Intestinais/microbiologia , Mucosa Intestinal/microbiologia , Animais , Autoimunidade , Diabetes Mellitus Tipo 1/imunologia , Homeostase , Humanos , Tolerância Imunológica , Imunomodulação , Inflamação/imunologia , Doenças Inflamatórias Intestinais/imunologia , Mucosa Intestinal/imunologiaRESUMO
The initiation and maintenance of adaptive immunity require multifaceted modes of communication between different types of immune cells, including direct intercellular contact, secreted soluble signaling molecules, and extracellular vesicles (EVs). EVs can be formed as microvesicles directly pinched off from the plasma membrane or as exosomes secreted by multivesicular endosomes. Membrane receptors guide EVs to specific target cells, allowing directional transfer of specific and complex signaling cues. EVs are released by most, if not all, immune cells. Depending on the type and status of their originating cell, EVs may facilitate the initiation, expansion, maintenance, or silencing of adaptive immune responses. This review focusses on EVs from professional antigen-presenting cells, their demonstrated and speculated roles, and their potential for cancer immunotherapy.
Assuntos
Apresentação de Antígeno/imunologia , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/metabolismo , Vesículas Extracelulares/metabolismo , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Transporte Biológico , Micropartículas Derivadas de Células/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Epiteliais/metabolismo , Exossomos/metabolismo , Antígenos de Histocompatibilidade/genética , Antígenos de Histocompatibilidade/imunologia , Humanos , Tolerância Imunológica , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Researchers are intensifying efforts to understand the mechanisms by which changes in metabolic states influence differentiation programs. An emerging objective is to define how fluctuations in metabolites influence the epigenetic states that contribute to differentiation programs. This is because metabolites such as S-adenosylmethionine, acetyl-CoA, α-ketoglutarate, 2-hydroxyglutarate, and butyrate are donors, substrates, cofactors, and antagonists for the activities of epigenetic-modifying complexes and for epigenetic modifications. We discuss this topic from the perspective of specialized CD4+ T cells as well as effector and memory T cell differentiation programs. We also highlight findings from embryonic stem cells that give mechanistic insight into how nutrients processed through pathways such as glycolysis, glutaminolysis, and one-carbon metabolism regulate metabolite levels to influence epigenetic events and discuss similar mechanistic principles in T cells. Finally, we highlight how dysregulated environments, such as the tumor microenvironment, might alter programming events.
Assuntos
Diferenciação Celular/genética , Diferenciação Celular/imunologia , Metabolismo Energético , Epigênese Genética , Animais , Biomarcadores , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Neoplasias/etiologia , Neoplasias/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
The ability of immune cells to survey tissues and sense pathologic insults and deviations makes them a unique platform for interfacing with the body and disease. With the rapid advancement of synthetic biology, we can now engineer and equip immune cells with new sensors and controllable therapeutic response programs to sense and treat diseases that our natural immune system cannot normally handle. Here we review the current state of engineered immune cell therapeutics and their unique capabilities compared to small molecules and biologics. We then discuss how engineered immune cells are being designed to combat cancer, focusing on how new synthetic biology tools are providing potential ways to overcome the major roadblocks for treatment. Finally, we give a long-term vision for the use of synthetic biology to engineer immune cells as a general sensor-response platform to precisely detect disease, to remodel disease microenvironments, and to treat a potentially wide range of challenging diseases.
Assuntos
Alergia e Imunologia , Vacinas Anticâncer/imunologia , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Biologia Sintética , Linfócitos T/imunologia , Animais , Engenharia Genética , Humanos , Ativação Linfocitária , Neoplasias/imunologia , Receptores de Antígenos de Linfócitos T/genética , Proteínas Recombinantes de Fusão/genética , Linfócitos T/transplanteRESUMO
Allogeneic chimeric antigen receptor (CAR)-T cells hold great promise for expanding the accessibility of CAR-T therapy, whereas the risks of allograft rejection have hampered its application. Here, we genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells using CRISPR-Cas9 to address the issue of immune rejection and treated one patient with refractory immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis with these cells. This study was registered at ClinicalTrials.gov (NCT05859997). The infused cells persisted for over 3 months, achieving complete B cell depletion within 2 weeks of treatment. During the 6-month follow-up, we observed deep remission without cytokine release syndrome or other serious adverse events in all three patients, primarily shown by the significant improvement in the clinical response index scores for the two diseases, respectively, and supported by the observations of reversal of inflammation and fibrosis. Our results demonstrate the high safety and promising immune modulatory effect of the off-the-shelf CAR-T cells in treating severe refractory autoimmune diseases.
Assuntos
Antígenos CD19 , Imunoterapia Adotiva , Miosite , Receptores de Antígenos Quiméricos , Escleroderma Sistêmico , Humanos , Antígenos CD19/imunologia , Antígenos CD19/metabolismo , Miosite/terapia , Miosite/imunologia , Escleroderma Sistêmico/terapia , Escleroderma Sistêmico/imunologia , Imunoterapia Adotiva/métodos , Feminino , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/metabolismo , Masculino , Pessoa de Meia-Idade , Adulto , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transplante HomólogoRESUMO
Defective host defenses later in life are associated with changes in immune cell activities, suggesting that age-specific considerations are needed in immunotherapy approaches. In this study, we found that PD-1 and CTLA4-based cancer immunotherapies are unable to eradicate tumors in elderly mice. This defect in anti-tumor activity correlated with two known age-associated immune defects: diminished abundance of systemic naive CD8+ T cells and weak migratory activities of dendritic cells (DCs). We identified a vaccine adjuvant, referred to as a DC hyperactivator, which corrects DC migratory defects in the elderly. Vaccines containing tumor antigens and DC hyperactivators induced T helper type 1 (TH1) CD4+ T cells with cytolytic activity that drive anti-tumor immunity in elderly mice. When administered early in life, DC hyperactivators were the only adjuvant identified that elicited anti-tumor CD4+ T cells that persisted into old age. These results raise the possibility of correcting age-associated immune defects through DC manipulation.