Enhancement of virus-specific expansion of transgenic CD8 T cells in aged mice by dendritic cells

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Abstract

Aging is associated with a decreased CD8 T cell response to multiple antigens and to virus infection. Although both intrinsic and extrinsic factors have been shown to contribute to the decrease, the mechanisms are still largely unknown. In this study, the role of dendritic cells (DCs) in the age-associated decrease was examined. Influenza-specific TCR transgenic CD8 T cells of young mice demonstrated limited expansion in response to influenza infection when adoptively transferred to aged compared to young mice. This decreased response in aged mice could be significantly enhanced when DCs of young mice were co-transferred. Co-transfer of DCs had no impact in young recipient mice. Adoptive transfer of the DCs also increased the endogenous CD8 T cell response of intact aged mice, although to a lesser degree. These results suggest that the diminished CD8 T cell response to virus infection in aged mice is partially attributable to age-associated changes in DCs.

Research highlights

▶ The role of dendritic cells (DCs) in the age-associated decrease was examined. ▶ Influenza-specific TCR transgenic CD8 T cells of young mice demonstrated limited expansion in response to influenza infection when adoptively transferred to aged compared to young mice. ▶ This decreased response in aged mice could be significantly enhanced when DCs of young mice were co-transferred. Co-transfer of DCs had no impact in young recipient mice. ▶ These results suggest that the diminished CD8 T cell response to virus infection in aged mice is partially attributable to age-associated changes in DCs.

Introduction

Aging is associated with a decreased CD8 T cell response to virus infection (Po et al., 2002, Kapasi et al., 2002, Jiang et al., 2009, Brien et al., 2009), although the mechanisms are still largely unclear (Linton et al., 2005). Using an adoptive transfer approach with two different viruses, we observed that the aged environment, regardless of genetic background of mice, significantly inhibits both clonal expansion and IFN-γ production by specific Tg CD8 T cells of young mice during virus infection (Jiang et al., 2009). These data indicate that alterations in the aged environment play an important role in the decreased specific CD8 T cell immunity to virus infection with aging.

Dendritic cells (DCs) are one component of the lymphoid environment that could contribute to the diminished response with aging. Several studies have described a reduced ability of unfractionated APCs or macrophages of aged mice to stimulate T cell effector function (Jiang et al., 2009, Plowden et al., 2004, Donnini et al., 2002, Beharka et al., 1997). Poor expression of co-stimulatory molecules, such as CD40 and CD86, on DCs of aged mice may result in failure to induce optimal effector T cell responses (Chiu et al., 2007, Varas et al., 2003). Recently, Grolleau-Julius et al. (2008) observed a decrease in DC-SIGN (CD209) expression in aged mice, which may contribute to impaired T cell response. In addition, adoptive transfer experiments show defective trafficking of DCs in vivo in aged mice (Linton et al., 2005, Grolleau-Julius et al., 2008). While some studies report a decline in function of mouse DCs (Sprecher et al., 1990, Villadsen et al., 1987, Haruna et al., 1995), other studies report no change (Tesar et al., 2006, Komatsubara et al., 1986). Similarly, no consensus has been reached concerning the function of DCs of humans (Lung et al., 2000, Shurin et al., 2007, Saurwein-Teissl et al., 1998). Our recent data (Jiang et al., 2009) suggest that the in vitro function of DCs remain intact with age: when equal numbers of purified DCs from young or aged mice were cultured with the same virus-specific CD8 T cells of young mice, the expansion of the CD8 T cells was similar, indicating that the APC function of DCs from aged mice remains intact in vitro. These results supported a previous study that showed the functions of DCs from aged mice remain intact even though there exists differences in the percentages of myeloid vs. lymphoid DCs and surface expression of MHC molecules on DCs between young and aged mice (Norian and Allen, 2004).

It has been reported that the number of DCs recovered from spleens of aged mice is decreased 30–50% compared to young mice (Linton et al., 2005). Our recent data also show that both BALB/c and B6 mice demonstrate a significantly decreased number of DCs in the spleen of aged compared to young mice (Jiang et al., 2009). This decreased number of DCs in aged mice may contribute to the inability of the aged environment to support maximal expansion of CD8 T cells in aged mice.

The current study was designed to determine if the number of DCs in aged mice was limiting T cell expansion. Utilizing Tg CD8 T cells specific for influenza as a model, we found that the diminished expansion of the Tg CD8 T cells that is observed in aged compared to young recipients after influenza virus infection was significantly enhanced in aged mice when DCs of young mice were co-transferred. A similar effect was not observed in young recipients. Interestingly, adoptive transfer of enriched DCs failed to significantly enhance the endogenous CD8 T cell response in aged mice. These results suggest that DCs in the aged environment are not sufficient to support the expansion of young CD8 T cells in response to antigen-specific challenge in this model influenza virus infection. However, since the diminished endogenous CD8 T cell response with aging cannot be enhanced by adoptively transferred DCs, either the number of DCs transferred needs to be larger, the transferred DCs do not migrate adequately, or the DCs cannot compensate for the intrinsic defect of CD8 T cells of aged mice.

Section snippets

Mice, virus and infection

Young (4-month-old) and aged (18–20-month-old) female wild type Thy1.2+ BALB/c mice were purchased from the NIA at Harlan Sprague Dawley (Indianapolis, IN). Six- to 8-week old female Thy1.1+ BALB/c ByJ Cl.1, Clone-4 (HA518–526 TCR Tg) mice, specific for influenza virus (Kreuwel et al., 2001), were acquired from Jackson laboratory (Bar Harbor, Maine). All mice were maintained in AAALAC-approved barrier facilities and all experiments were conducted with the approval of the Institutional Animal

Effect of adoptively transferred DCs on expansion of young Tg CD8 T cells in aged mice

In a previous study, we found that the aged environment significantly inhibits clonal expansion of and IFN-γ production by specific Tg CD8 T cells of young mice during virus infection (Po et al., 2002, Jiang et al., 2009). To determine if the inability of the aged environment to support expansion of young Tg CD8 T cells was due to a deficiency of DCs, we co-transferred 1 × 104 purified TCR Tg CD8 T cells of young Clone-4 mice (Thy1.1+), which specifically recognize influenza virus HA518–526

Discussion

It is known that CD8 T cell immune response to virus infection is impaired with aging (Po et al., 2002, Kapasi et al., 2002, Jiang et al., 2009, Brien et al., 2009), and both intrinsic and extrinsic factors contribute to this defect (Linton et al., 2005). Many studies have been performed in vitro to assess the mechanisms of age-related immunological alteration (Jiang et al., 2009, Jiang et al., 2003, Ahmed et al., 2009). Only limited in vivo evidence has been available to demonstrate that the

Acknowledgments

This work was supported by National Institutes of Health Grant AG14913. We thank MHC Tetramer Core Facilities of NIH at Atlanta for kindly providing H-2Kd HA518–526 tetramer.

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