Partial Activation of Neonatal CD11c+ Dendritic Cells and Induction of Adult-Like CD8+ Cytotoxic T Cell Responses by Synthetic Microspheres

Abstract

Neonatal cytotoxic T cell responses have only been elicited to date with immunogens or delivery systems inducing potent direct APC activation. To define the minimal activation requirements for the induction of neonatal CD8+ cytotoxic responses, we used synthetic microspheres (MS) coated with a single CD8+ T cell peptide from lymphocytic choriomeningitis virus (LCMV) or HIV-1. Unexpectedly, a single injection of peptide-conjugated MS without added adjuvant induced CD4-dependent Ag-specific neonatal murine cytotoxic responses with adult-like CTL precursor frequency, avidity for Ag, and frequency of IFN-γ-secreting CD8+ splenocytes. Neonatal CD8+ T cell responses to MS-LCMV were elicited within 2 wk of a single immunization and, upon challenge, provided similar protection from viral replication as adult CTLs, demonstrating their in vivo competence. As previously reported, peptide-coated MS elicited no detectable activation of adult CD11c+ dendritic cells (DC). In contrast, CTL responses were associated with a partial activation of neonatal CD11c+ DC, reflected by the up-regulation of CD80 and CD86 expression but no concurrent changes in MHC class II or CD40 expression. However, this partial activation of neonatal DC was not sufficient to circumvent the requirement for CD4+ T cell help. The effective induction of neonatal CD8+ T cell responses by this minimal Ag delivery system demonstrates that neonatal CD11c+ DC may mature sufficiently to stimulate naive CD8+ neonatal T cells, even in the absence of strong maturation signals.

Protracted Course of Lymphocytic Choriomeningitis Virus WE Infection in Early Life: Induction but Limited Expansion of CD8+Effector T Cells and Absence of Memory CD8+T Cells

“…3D), and their levels of expression of the CD25 IL-2 receptor (data not shown) (17) are also similar. LCMVnp118-126-specific CD8 ϩ T cells also expand normally in response to immunization with inert antigen delivery systems presenting LCMV epitopes (41,57). Although the rapid clearance of apoptotic cells in vivo may lead to the underestimation of apoptosis by ex vivo annexin staining, the rate of apoptosis was similar in both age groups, which is in accordance with the low levels of expression of proapoptotic genes by LCMV-specific CD8 ϩ T cells during the early stages of infection (82).…”

“…This age was chosen to avoid the risk of thymic infection (Յ24 h) and the immune limitations that are notoriously associated with the neonatal (Յ7 days) period and was experimentally defined. Indeed, 2-week-old BALB/c mice are capable of rais- ing adult-like LCMV-specific CD8 ϩ T cells in response to peptide-loaded virus-like particles (41) or microspheres (57). In contrast to neonatal mice, 2-week-old mice raise adult-like CD4 ϩ Th1 cells in response to most antigen delivery systems (reviewed in reference 62 and our unpublished data).…”

“…Neonatal murine DCs competently induce adult-like CD8 ϩ T-cell responses to numerous vaccine antigens (reviewed in reference (2), including to the LCMV peptide used in this study (41,57). However, the DC activation pattern could differ during early life and adult LCMV infections, resulting in differences in the production of interferons.…”

“…ϩ T-cell neonatal responses similar to those of adults may even be elicited by synthetic microspheres that do not elicit strong Th1 responses (7,57).…”

Multifunctional dendritic cell-targeting polymeric microparticles

“…86 Additionally, other microparticle modification approaches to target DCs include surface-tethering antibodies targeting CD40, and the α V β 3 , α V β 5 and CD11c integrins, reporting differential levels of DC activation for each. 130,131 This is an informative comparison, as the functional consequences of DC integrin binding is not well understood, 132,133 and are currently under investigation. indicating uptake and migration by phagocytes.…”