Neuropilin-1 Expression Is Induced on Tolerant Self-Reactive CD8+ T Cells but Is Dispensable for the Tolerant Phenotype
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Abstract:
Establishing peripheral CD8+ T cell tolerance is vital to avoid immune mediated destruction of healthy self-tissues. However, it also poses a major impediment to tumor immunity since tumors are derived from self-tissue and often induce T cell tolerance and dysfunction. Thus, understanding the mechanisms that regulate T cell tolerance versus immunity has important implications for human health. Signals received from the tissue environment largely dictate whether responding T cells become activated or tolerant. For example, induced expression and subsequent ligation of negative regulatory receptors on the surface of self-reactive CD8+ T cells are integral in the induction of tolerance. We utilized a murine model of T cell tolerance to more completely define the molecules involved in this process. We discovered that, in addition to other known regulatory receptors, tolerant self-reactive CD8+ T cells distinctly expressed the surface receptor neuropilin-1 (Nrp1). Nrp1 was highly induced in response to self-antigen, but only modestly when the same antigen was encountered under immune conditions, suggesting a possible mechanistic link to T cell tolerance. We also observed a similar Nrp1 expression profile on human tumor infiltrating CD4+ and CD8+ T cells. Despite high expression on tolerant CD8+ T cells, our studies revealed that Nrp1 had no detectable role in the tolerant phenotype. Specifically, Nrp1-deficient T cells displayed the same functional defects as wild-type self-reactive T cells, lacking in vivo cytolytic potential, IFNγ production, and antitumor responses. While reporting mostly negative data, our findings have therapeutic implications, as Nrp1 is now being targeted for human cancer therapy in clinical trials, but the precise molecular pathways and immune cells being engaged during treatment remain incompletely defined.Keywords:
Peripheral tolerance
In the immune system, Neuropilin-1 (Nrp1) is a molecule that plays an important role in establishing the immunological synapse between dendritic cells (DCs) and T cells. Recently, Nrp1 has been identified as a marker that seems to distinguish natural T regulatory (nTreg) cells, generated in the thymus, from inducible T regulatory (iTreg) cells raised in the periphery. Given the crucial role of both nTreg and iTreg cells in the generation and maintenance of immune tolerance, the ability to phenotypically identify each of these cell populations in vivo is needed to elucidate their biological properties. In turn, these properties have the potential to be developed for therapeutic use to promote immune tolerance. Here we describe the nature and functions of Nrp1, including its potential use as a therapeutic target in transplantation tolerance.
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Peripheral tolerance
Central tolerance
Self Tolerance
Clonal deletion
Immunologic Tolerance
Clonal anergy
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Peripheral tolerance
Homeostasis
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Dendritic cells(DC) are the most potent professional antigen presenting cells, which play a key role in the formation and maintenance of the central and peripheral immune tolerance, and can be modified by a variety of methods for induction of peripheral tolerance.Tolerogenic DC have become a powerful tool and target for immune therapy by inducing immune tolerance.
Key words:
Tolerogenic dendritic cells; Autoimmune
Peripheral tolerance
Self Tolerance
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Mucosal and systemic administrations of high dose antigens induce long-lasting peripheral T cell tolerance. We and others have shown that high dose peripheral T cell tolerance is mediated by anergy or deletion and is preceded by T cell activation. Co-stimulatory molecules B7-1 (CD80)/B7-2 (CD86) and their counter-receptors CD28/CTLA-4 play pivotal roles in T cell activation and immune regulation. In the present study, we examined the roles of the B7 co-stimulation pathway in the generation of high dose peripheral T cell tolerance. We found that blocking B7:CD28/CTLA-4 interaction at the time of tolerance induction partially prevented T cell tolerance, whereas selective blockade of B7:CTLA-4 interaction completely abrogated peripheral T cell tolerance induced by either oral or i.p. antigens. These results suggest that CTLA-4-mediated feedback regulation plays a crucial role in the induction of high dose peripheral T cell tolerance.
Peripheral tolerance
CD80
CD86
CTLA-4
Co-stimulation
Clonal anergy
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Immune tolerance includes central immune tolerance and peripheral immune tolerance.The major mechanism of central tolerance is mainly due to clonal deletion of self-antigen-reactive T cells in the thymus.Peripheral tolerance mechanisms involve the deletion of peripheral mature T cells.The autoimmune regulator (Aire) plays an important role in the establishment and maintenance of central and peripheral immunological tolerance.Monoallelic mutations in Aire could cause autoimmune diseases.A large number of studies have shown that Aire may become a new target for the induction of tolerance in organ transplantation and the treatment for autoimmune diseases.
Key words:
Autoimmune regulator; Immunological tolerance; Negative selection; Transplant rejection reaction
Peripheral tolerance
Autoimmune regulator
Central tolerance
Clonal deletion
Self Tolerance
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In the past, tolerance mechanisms have focused on processes that involve elimination (deletion) or paralysis (anergy) of immune responses. It is now becoming clearer that peripheral tolerance to antigen depends on the generation of regulatory cells that function to maintain the tolerant state. The development of peripheral tolerance may require that the immune system utilize several strategies, including deletion, anergy, and immunoregulatory pathways, and these strategies may overlap. Recent investigations using animal models of transplantation tolerance have demonstrated that immunoregulatory CD4 mechanisms may play a central role in limiting organ-destructive immune responses. In this Overview, we discuss the rationale behind the need for invoking active regulatory mechanisms in peripheral immunologic tolerance and summarize the data that support or refute a CD4 regulatory mechanism.
Peripheral tolerance
Clonal deletion
Central tolerance
Clonal anergy
Limiting
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Peripheral tolerance
Clonal deletion
Genetic predisposition
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Tolerance is defined as a mechanism by which a potentially injurious immune response is prevented, suppressed, or shifted to a non-injurious type of response. Immune tolerance was traditionally divided into two categories: central tolerance, whereby tolerance is inducedviapresentation of foreign antigens in the thymus; and peripheral tolerance where tolerance is induced outside the thymus [1]. Tolerance can also be divided into "dominant" and "passive" types of tolerance based on the mechanisms of tolerance induction. A "dominant" type of tolerance involves production of suppressor cells that suppress the anti-foreign antigen immune response, and which can be transferred. A "passive" type of immune tolerance involves immune ignorance or clonal deletion and is non-transferable [1]. Tolerance is today viewed as an active process. The current understanding of immunological tolerance does not simply distinguish between self and non-self, but also reacts to danger signals that confront the immune system [2, 3]. Auto reactive cells, present in all individuals and reacting with brain antigens, thyroglobulin, serum albumin, collagen and other auto-antigens, are not deleted. These cells, under normal conditions, remain harmless. Cells reactive with self may have an important function in maintaining tissue homeostasis. Thus, immunological tolerance, requiring an active process that functions during the entire life of the organism, cannot rely solely on neonatal deletion.
Peripheral tolerance
Clonal deletion
Immunologic Tolerance
Self Tolerance
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The major challenge in the treatment of autoimmune diseases is the restoration of the impaired peripheral immune tolerance that always accompanies the development of such diseases. Here, we show that small splenic peptides (SSPs) of whole spleen extract efficiently suppress the development of psoriatic arthritis in vivo, even in the presence of sustained levels of pro-inflammatory cytokines. SSPs target dendritic cells (DCs) and convert them into tolerogenic cells, which in turn differentiate naive CD4+ cells into Foxp3-expressing T regulatory cells (Tregs). The latter requires direct contact between SSP-activated DCs and naive CD4+ T cells via PD-1 and CTLA4 immune checkpoint receptors of T cells. Finally, depletion of Foxp3+ Tregs in vivo abrogated the protective effect of SSPs on psoriatic arthritis development. We hypothesize that SSPs represent an intrinsic component of the adaptive immune system responsible for the physiological maintenance of peripheral tolerance and that therapeutically administered SSPs are able to restore imbalanced peripheral tolerance in autoimmune diseases.
Peripheral tolerance
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