The frail elderly: role of dendritic cells in the susceptibility of infection

doi:10.1016/S0047-6374(02)00033-7

Mechanisms of Ageing and Development

Volume 123, Issue 8, 30 April 2002, Pages 955-962

https://doi.org/10.1016/S0047-6374(02)00033-7 Get rights and content

Abstract

The decline in immunity in the elderly has largely been attributed to impairment of T cell mechanisms. This seems reasonable since the thymus involutes with age, so that the number of naı̈ve cells to respond to new foreign antigens also declines. However, little is known about how aging affects antigen-presenting cells (APC) that are responsible for the initiation and outcome of effector T cell immune responses. This review focuses on the age-related alterations of a key APC, the dendritic cell (DC). Recent findings suggest that interleukin-10, a key cytokine that can suppress cell mediated immunity and maturation of DC subsets, is elevated in the very healthy elderly. However, production of IL-12, required for the initiation of T cell immune responses, declines in frail elderly along with DC antigen presenting function. These findings suggest that shifts in IL-10 and IL-12 may not only directly influence immune response but may also alter the balance and maturation of DC subsets. Finally, study of immunologic differences between the very healthy and frail elderly may reveal important changes in DC function and regulation influenced by age and/or environment (disease, nutrition, medications, etc.).

Introduction

Increased morbidity and mortality for many infectious diseases is one of the inevitable plights of the aging process, and the incidence and severity of infection is even higher among institutionalized patients or frail elderly subjects (Castle et al., 1990). Age-related decline of the immune system, alterations in nutrition, accumulation of chronic illness and immunosuppression (iatrogenic or acquired) may be some of the factors that contribute to this excess morbidity and mortality (Makinodan and Kay, 1980, Miller, 1991). Since T cell immunity is closely linked to resistance against infection, a tremendous amount of effort has been expended over the past three decades to the problem of age-related decline in T cell-dependent immune response. Age-related decline in T cell reactivity to foreign antigen, cytokine production, signal transduction and activation pathways have been reported in several recent reviews (Chakravarti and Abraham, 1999, Linton and Thoman, 2001, Pawelec et al., 2001). In contrast, remarkably little is known about how aging affects antigen-presenting cells (APC), the key cells responsible for the induction of T cell dependent immune responses. Therefore, this perspective will focus on the aging APC, specifically the dendritic cells (DC), and their role in immunosenescence.

Section snippets

Importance of studying frail elderly

Frail elderly subjects are at increased risk and severity to infections (Castle et al., 1990). Mortality from community acquired pneumonia has actually increased in the elderly (>70 years) since the inception of antibiotics, highlighting the importance of preventive practices including immunization. Unfortunately, frail elderly have responded poorly to immunization, and clinical trials to improve response to vaccine have had negligible clinical impact (Klinman and Liu, 1996, Duchateau et al.,

Aging and antigen-presenting cells (APC)

T cells must first be activated by functional APC to initiate an appropriate immune response. APC, composed of macrophages/monocytes, B cells and DC, initially take up and process antigens before presenting them to specific T cells along with appropriate co-stimulatory molecules and cytokines. Such APC activities initiate and determine the outcome of effector T cell responses. Many years ago, we attempted to resolve this issue of whether aging affected the APC in its ability to stimulate T

Cytokines and dendritic cells

The regulation of the immune system and effector functions of T cells are mediated by cytokines. The recent division of T cells into distinct functional subsets (Th1 and Th2) based upon cytokine profiles has been crucial to our understanding of immune responses (Mosmann et al., 1986). Th1 cells produce IL-2, IL-12 and IFN-γ, resulting in T cell proliferation and macrophage activation, features of cell-mediated immunity. In contrast, Th2 cell produce IL-4, IL-5 and IL-10, cytokines which augment

Enhancement of immune responses

In vitro enhancement of immune responses may provide opportunities to determine the role of APC in age-related decline in host immunity. We have shown that neutralization of IL-10 with monoclonal antibody (mAb) increased the proliferative response of peripheral blood mononuclear cells (PBMC) of elderly subjects (Castle et al., 1999a, Castle et al., 1999b). Th1/Th2 cytokines are cross-regulatory, so that Th1 cytokine may also provide a strategy to down-regulate IL-10 production and/or effect. It

Concluding remarks

Despite unprecedented improvements in life expectancy, increased risk and severity to infection remain prevalent drawbacks associated with aging (Report of the Task Force on Immunology and Aging, 1996). Therefore, there has been a great movement to vaccinate the elderly for the prevention of common infections. Unfortunately, the elderly have responded poorly to immunization, and clinical trials to improve response to vaccine have had negligible clinical impact (Klinman and Liu, 1996).

One of the

Acknowledgments

This work was supported by the National Institute of Aging and Department of Veterans Affairs Merits Award TAB13.

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The frail elderly: role of dendritic cells in the susceptibility of infection

Abstract

Introduction

Section snippets

Importance of studying frail elderly

Aging and antigen-presenting cells (APC)

Cytokines and dendritic cells

Enhancement of immune responses

Concluding remarks

Acknowledgments

Mech. Ageing Dev.

Mech. Ageing Dev.

Mech. Ageing Dev.

Mech. Ageing Dev.

Cytokine

Mech. Ageing Dev.

Adv. Immunol.

Int. Rev. Cytol.

Mech. Ageing Dev.

Mech. Ageing Dev.

Immunol. Lett.

Mech. Ageing Dev.

Hum. Immunol.

J. Invest. Dermatol.

Exp. Gerontol.

Age-related impaired proliferation of peripheral blood mononuclear cells is associated with an increase in both IL-10 and IL-12

Exp. Gerontol.

Role of T cells and adherent cells in age-related decline in murine interleukin 2 production

J. Immunol.

Regulatory activity of autocrine IL-10 on dendritic cell functions

J. Immunol.

Modulation of immune response in aged humans through different administration modes of thymopentin

Surv. Immunol. Res.