Regulation of immune cell homeostasis by type I interferons

doi:10.1016/j.cytogfr.2010.05.002

Cytokine & Growth Factor Reviews

Volume 21, Issue 4, August 2010, Pages 227-236

https://doi.org/10.1016/j.cytogfr.2010.05.002 Get rights and content

Abstract

Although initially identified and best characterized for their role in innate antiviral defence, type I interferons (IFN-I) are also known to have an important impact on the adaptive immune response. In part, this is linked to another long-recognised property of IFN-I, namely their ability to modify cellular proliferation and survival. Here, we review the influence of IFN-I on immune cell homeostasis, focusing on their effects on T cells and antigen-presenting cells.

Introduction

The immune system comprises a complex array of cell types that exist in a dynamic equilibrium. Under steady-state conditions, cell numbers remain roughly constant. Thus, while the life span and turnover of different cell types varies, there is an overall balance in which the loss of effete cells is offset by the input of new cells generated either by differentiation from precursors or by proliferation of mature cells. This balance is maintained based on a limiting availability of growth and survival factors that support these cells. Under conditions of immune activation, for example in response to infection, the equilibrium is altered, and lymphocyte numbers can increase dramatically. During such an event, signals for cell proliferation, differentiation and death are regulated to produce a large arsenal of effector lymphocytes that can combat the pathogen. Since the cost of maintaining such elevated cell numbers is high – in terms of energy expenditure and potentially damaging immune inflammation – cell numbers decline rapidly following clearance or control of the pathogen to again reach equilibrium, with cell numbers resembling pre-infection levels. However, important differences from the pre-immune state are apparent post-pathogen clearance. In particular, increased numbers of lymphocytes capable of recognising pathogen antigens persist and contribute to long-lasting immunological memory.

Hence, one key to proper functioning of the immune system is precise control of cell numbers through the regulation of cell production, proliferation and death. Given the crucial importance of rapid changes in cellularity in the face of infection, it is not surprising that immune cell turnover is influenced by factors that signal the presence of pathogens. Here we review the evidence that type I interferons (which include multiple IFN-αs, IFN-β and several closely related genes, hereafter referred to collectively as IFN-I), the production of which increases rapidly in response to both viral and bacterial infection, influence the function of the immune system through the regulation of cellular homeostasis. We focus primarily on two cell types: dendritic cells (DC), which are key antigen-presenting cells involved in the initiation of immune responses, and T cells, key effector and regulatory cells of the response.

Section snippets

Ontogeny of dendritic cells

Dendritic cells are hematopoietic cells that belong to the antigen-presenting cell (APC) family, which also includes B cells and macrophages. DC represent a heterogeneous cohort of cells located in both lymphoid and non-lymphoid tissues at sites that are optimal for capture of foreign antigens and contact with other immune cells. In mice lymphoid tissue DC include two main blood-borne subsets: plasmacytoid DC (pDC) and conventional DC (cDC), with the latter further subdivided into CD8⁺CD4⁻CD11b⁻

Dendritic cell homeostasis and survival

The homeostasis of steady-state lymphoid organ pDC and cDC in vivo is primarily regulated by Flt3-L which triggers proliferative DC precursors expressing Flt3 in BM, blood and lymphoid organs. In the steady-state, the various DC populations recycle with different kinetics, reflecting their diverse lifespan in vivo. The turnover of DC populations in vivo has typically been assessed using DNA precursors, particularly bromo-deoxyuridine (BrdU), which is incorporated into dividing DC progenitors;

Regulation of dendritic cell homeostasis and lifespan by type I IFN

Evidence from a variety of studies indicates that IFN-I can regulate the lifespan of various cell types. IFN-I not only affect cell growth and division but also influence cell survival. For example, IFN-I have been reported to trigger apoptosis of tumour cells as well as virus-infected cells [31]. IFN-I have also been found to affect the lifespan of non-malignant cells, such as T lymphocytes and other immune cells, thus contributing to the alterations in immune cell homeostasis that occur after

T cell development

T lymphocytes are produced from progenitors through a series of well-described maturation steps in the thymus [48]. The maturation process includes selection of T cells based on the specificity of their T cell antigen receptor (TCR), which in the predominant population of T cells comprises α- and β-chains in its antigen recognition unit (αβTCR). Selection is necessary because the coding sequence (and hence antigen-specificity) of the αβTCR is generated randomly through variable recombination of

T cell homeostasis and memory

Following export from the thymus, T lymphocytes adopt a pattern of migration in which they continuously recirculate between blood and lymph, exiting the blood stream into lymph nodes via high endothelial venules and returning via the thoracic duct. While traversing the secondary lymphoid organs (spleen, LN), T cells are able to scan the surface of APC for the presentation of foreign antigens. Until such time as they encounter antigens for which their TCR have sufficient affinity to trigger

Regulation of T cell homeostasis by IFN-I

IFN-I have been shown to impact T cell homeostasis at multiple levels. Given the key role of IFN-I in the innate response to infection, it is not surprising that these effects relate mainly to changes in T cell dynamics during the course of immune responses. Indeed, IFN-I have been shown to enhance the magnitude of primary and memory CD4⁺ and CD8⁺ T cell responses [40], [65], [66], [67], [68], [69].

One important factor in the immune-stimulatory activity of IFN-I is their ability to modify DC

Concluding remarks

In the past two decades, the mechanisms linking the innate response to infection and the generation of adaptive immune responses have become increasingly well understood. IFN-I are key cytokines involved in this process; they are induced rapidly after infection and are critical mediators of innate antiviral defense, yet also have a major impact on T and B cell-mediated immunity. Integral to their role in adaptive immunity is the impact that IFN-I have on DC homeostasis and function. DC are the

Acknowledgements

Supported by grants from the Italian Association for Cancer Research (AIRC) and by the European Community 7th Framework Program.

Fabrizio Mattei graduated from Università “La Sapienza” in Rome and completed his specialization in biotechnologies and oncology at the same university. In 2000, he became a fellow at the Edward Jenner Institute for Vaccine Research in David Tough's laboratory, where he acquired experience in the field of dendritic cell immunology. He is currently a senior researcher at the Istituto Superiore di Sanità in Rome where he has focused on the molecular interactions between dendritic cells and type I

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Mini reviewRegulation of immune cell homeostasis by type I interferons

Abstract

Introduction

Section snippets

Ontogeny of dendritic cells

Dendritic cell homeostasis and survival

Regulation of dendritic cell homeostasis and lifespan by type I IFN

T cell development

T cell homeostasis and memory

Regulation of T cell homeostasis by IFN-I

Concluding remarks

Acknowledgements

Characterization of an immediate splenic precursor of CD8+ dendritic cells capable of inducing antiviral T cell responses

J Immunol

The origin and development of nonlymphoid tissue CD103+ DCs

J Exp Med

CD103− and CD103+ bronchial lymph node dendritic cells are specialized in presenting and cross-presenting innocuous antigen to CD4+ and CD8+ T cells

J Immunol

Heterogeneity of thymic dendritic cells

Semin Immunol

Dendritic cell homeostasis

Blood

Origin of dendritic cells in peripheral lymphoid organs of mice

Nat Immunol

Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo

Nat Immunol

Characterization of a common precursor population for dendritic cells

Nature

Characterization of distinct conventional and plasmacytoid dendritic cell-committed precursors in murine bone marrow

J Immunol

In vivo analysis of dendritic cell development and homeostasis

Science

In situ replication of immediate dendritic cell (DC) precursors contributes to conventional DC homeostasis in lymphoid tissue

J Immunol

Intrasplenic steady-state dendritic cell precursors that are distinct from monocytes

Nat Immunol

Antigen transmission by replicating antigen-bearing dendritic cells

J Immunol

Intrinsic lymphotoxin-beta receptor requirement for homeostasis of lymphoid tissue dendritic cells

Immunity

Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells

Nat Immunol

Development of dendritic-cell lineages

Immunity

The development, maturation, and turnover rate of mouse spleen dendritic cell populations

J Immunol

Mouse plasmacytoid cells: long-lived cells, heterogeneous in surface phenotype and function, that differentiate into CD8(+) dendritic cells only after microbial stimulus

J Exp Med

Developmental kinetics and lifespan of dendritic cells in mouse lymphoid organs

Blood

Anatomical origin of dendritic cells determines their life span in peripheral lymph nodes

J Immunol

Regulation of the lifespan in dendritic cell subsets

Mol Immunol

Apoptosis and the homeostatic control of immune responses

Curr Opin Immunol

Inducible IL-2 production by dendritic cells revealed by global gene expression analysis

Nat Immunol

Bcl-2 controls dendritic cell longevity in vivo

J Immunol

A Bcl-2-dependent molecular timer regulates the lifespan and immunogenicity of dendritic cells

Nat Immunol

Bcl-xL is critical for dendritic cell survival in vivo

J Immunol

Deficiency of Bim in dendritic cells contributes to overactivation of lymphocytes and autoimmunity

Blood

Regulation of dendritic cell survival and cytokine production by osteoprotegerin

J Leukoc Biol

Homeostasis of dendritic cells in lymphoid organs is controlled by regulation of their precursors via a feedback loop

Blood

Lack of conventional dendritic cells is compatible with normal development and T cell homeostasis, but causes myeloid proliferative syndrome

Immunity

Interferons and apoptosis

J Interferon Cytokine Res

IFNalpha activates dormant haematopoietic stem cells in vivo

Nature

Interferon regulatory factor-2 protects quiescent hematopoietic stem cells from type I interferon-dependent exhaustion

Nat Med

Cyclophosphamide induces type I interferon and augments the number of CD44(hi) T lymphocytes in mice: implications for strategies of chemoimmunotherapy of cancer

Blood

Mini review
Regulation of immune cell homeostasis by type I interferons

Bcl-x_L is critical for dendritic cell survival in vivo