Dendritic cells (DCs) have several functions in innate and adaptive immunity. In addition, there is increasing evidence that DCs in situ induce antigen-specific unresponsiveness or tolerance in central lymphoid organs and in the periphery. In the thymus DCs generate tolerance by deleting self-reactive T cells. In peripheral lymphoid organs DCs also induce tolerance to antigens captured by receptors that mediate efficient uptake of proteins and dying cells. Uptake by these receptors leads to the constitutive presentation of antigens on major histocompatibility complex (MHC) class I and II products. In the steady state the targeting of DC antigen capture receptors with low doses of antigens leads to deletion of the corresponding T cells and unresponsiveness to antigenic rechallenge with strong adjuvants. In contrast, if a stimulus for DC maturation is coadministered with the antigen, the mice develop immunity, including interferon-gamma-secreting effector T cells and memory T cells. There is also new evidence that DCs can contribute to the expansion and differentiation of T cells that regulate or suppress other immune T cells. One possibility is that distinct developmental stages and subsets of DCs and T cells can account for the different pathways to peripheral tolerance, such as deletion or suppression. We suggest that several clinical situations, including autoimmunity and certain infectious diseases, can be influenced by the antigen-specific tolerogenic role of DCs.

https://digitalcommons.rockefeller.edu/cgi/viewcontent.cgi?article=1153&context=steinman-publications

Tolerogenic dendritic cells.

Forkhead box P3 (FOXP3)(+) regulatory T (T(Reg)) cells are potent mediators of dominant self tolerance in the periphery. But confusion as to the identity, stability and suppressive function of human T(Reg) cells has, to date, impeded the general therapeutic use of these cells. Recent studies have suggested that human T(Reg) cells are functionally and phenotypically diverse. Here we discuss recent findings regarding human T(Reg) cells, including the ontogeny and development of T(Reg) cell subsets that have naive or memory phenotypes, the unique mechanisms of suppression mediated by T(Reg) cell subsets and factors that regulate T(Reg) cell lineage commitment. We discuss future studies that are needed for the successful therapeutic use of human T(Reg) cells.

FOXP3 + regulatory T cells in the human immune system

Dendritic cells (DCs) orchestrate a repertoire of immune responses that bring about resistance to infection and silencing or tolerance to self. In the settings of infection and cancer, microbes and tumours can exploit DCs to evade immunity, but DCs also can generate resistance, a capacity that is readily enhanced with DC-targeted vaccines. During allergy, autoimmunity and transplant rejection, DCs instigate unwanted responses that cause disease, but, again, DCs can be harnessed to silence these conditions with novel therapies. Here we present some medical implications of DC biology that account for illness and provide opportunities for prevention and therapy.

Taking dendritic cells into medicine

Memory CD8 T cells are a critical component of protective immunity, and inducing effective memory T-cell responses is a major goal of vaccines against chronic infections and tumours. Considerable effort has gone into designing vaccine regimens that will increase the magnitude of the memory response, but there has been minimal emphasis on developing strategies to improve the functional qualities of memory T cells. Here we show that mTOR (mammalian target of rapamycin, also known as FRAP1) is a major regulator of memory CD8 T-cell differentiation, and in contrast to what we expected, the immunosuppressive drug rapamycin has immunostimulatory effects on the generation of memory CD8 T cells. Treatment of mice with rapamycin following acute lymphocytic choriomeningitis virus infection enhanced not only the quantity but also the quality of virus-specific CD8 T cells. Similar effects were seen after immunization of mice with a vaccine based on non-replicating virus-like particles. In addition, rapamycin treatment also enhanced memory T-cell responses in non-human primates following vaccination with modified vaccinia virus Ankara. Rapamycin was effective during both the expansion and contraction phases of the T-cell response; during the expansion phase it increased the number of memory precursors, and during the contraction phase (effector to memory transition) it accelerated the memory T-cell differentiation program. Experiments using RNA interference to inhibit expression of mTOR, raptor (also known as 4932417H02Rik) or FKBP12 (also known as FKBP1A) in antigen-specific CD8 T cells showed that mTOR acts intrinsically through the mTORC1 (mTOR complex 1) pathway to regulate memory T-cell differentiation. Thus these studies identify a molecular pathway regulating memory formation and provide an effective strategy for improving the functional qualities of vaccine- or infection-induced memory T cells.

/pdf/mtor-regulates-memory-cd8-t-cell-differentiation-46pb3qxcnz.pdf

mTOR regulates memory CD8 T-cell differentiation

Dendritic cells (DCs) are central in the orchestration of the various forms of immunity and tolerance. Their immunoregulatory role mainly relies on the ligation of specific receptors that initiate and modulate DC maturation resulting in the development of functionally different effector DC subsets that selectively promote T helper 1 (TH1)-, TH2- or regulatory T-cell responses. These DC-priming receptors include pattern recognition receptors (PRRs), which discriminate between (groups of) pathogens, as well as receptors that bind tissue factors that are produced either constitutively or in response to infection with pathogens, and characterize the type of tissue and the pathogen-specific response pattern of this tissue. Although it is becoming increasingly clear that the selective development of T-cell-polarizing DC subsets is related to the ligation of particular receptors that are involved in DC maturation, several inconsistencies with this concept remain.

Dendritic-cell control of pathogen-driven T-cell polarization.

Whether epithelial cells play a role in triggering the immune cascade leading to T helper 2 (T(H)2)-type allergic inflammation is not known. We show here that human thymic stromal lymphopoietin (TSLP) potently activated CD11c(+) dendritic cells (DCs) and induced production of the T(H)2-attracting chemokines TARC (thymus and activation-regulated chemokine; also known as CCL17) and MDC (macrophage-derived chemokine; CCL22). TSLP-activated DCs primed naive T(H) cells to produce the proallergic cytokines interleukin 4 (IL-4), IL-5, IL-13 and tumor necrosis factor-alpha, while down-regulating IL-10 and interferon-gamma. TSLP was highly expressed by epithelial cells, especially keratinocytes from patients with atopic dermatitis. TSLP expression was associated with Langerhans cell migration and activation in situ. These findings shed new light on the function of human TSLP and the role played by epithelial cells and DCs in initiating allergic inflammation.

/pdf/human-epithelial-cells-trigger-dendritic-cell-mediated-4jusdw5piq.pdf

Human epithelial cells trigger dendritic cell–mediated allergic inflammation by producing TSLP

T cell homeostasis is a self-regulating process for maintaining the size of the peripheral T cell pool. Although dendritic cells (DCs) seem to be important in T cell homeostasis, the molecular regulation of DC-mediated T cell homeostasis is unknown. We show that human DCs activated by thymic stromal lymphopoietin (TSLP) induced a robust expansion of autologous CD4(+) T cell populations, which depended on self peptide-major histocompatibility complex. The proliferating T cells adopted and maintained a central memory polyclonal phenotype and could differentiate into T helper type 1 or type 2 effector cells. These results, together with findings of TSLP expression in epithelial cells of mucosal lymphoid tissues and thymus, indicate that TSLP is involved in DC-mediated CD4(+) T cell homeostasis.

Human thymic stromal lymphopoietin promotes dendritic cell-mediated CD4+ T cell homeostatic expansion.

PROBLEM TO BE SOLVED: To provide: methods of modulating dendritic cell activity using agonists or antagonists of a mammalian cytokine; and methods of treating immune disorders.SOLUTION: A method of modulating antigen presenting cell (APC) priming of a T cell comprises contacting the APC with: a) an agonist of TSLP/IL-50 (SEQ ID NO:1) or an agonist of TSLP/IL-50 receptor (TSLP/IL-50R) (SEQ ID NOs:2, 3); or b) an antagonist of TSLP/IL-50 (SEQ ID NO:1) or an antagonist of TSLP/IL-50R (SEQ ID NOs:2, 3).

Mammalian cytokine and uses of related reagents

Verwendung von mit Zytokinen verwandten Reagentien von Säugetieren

L'invention a trait a des procedes de modulation de l'activite des cellules dendritiques au moyen d'agonistes et d'antagonistes d'une cytokine mammifere. L'invention concerne egalement des methodes de traitement de troubles immunitaires.

Utilisations d'une cytokine mammifere et reactifs associes

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