Efficient migration of dendritic cells toward lymph node chemokines and induction of TH1 responses require maturation stimulus and apoptotic cell interaction

Abstract

IntroductionMyeloid dendritic cells (DCs) have the unique ability to activate naive T cells and, as such, can be tailored to initiate an immune response against neoantigens. 1 Once loaded with antigens in peripheral tissues, DCs must migrate to secondary lymphoid organs and reach a fully mature functional stage to recruit rare naive T cells. 2 In the past decade, in vitro-generated DCs have been involved as cell adjuvants in multiple tumor vaccination trials to trigger antitumor immune responses and tumor regression. 3 For tumor vaccination purposes, autologous DCs are generated either from CD34 ϩ progenitors 4 or from peripheral blood monocytes differentiated in the presence of granulocyte macrophage-colonystimulating factor (GM-CSF) and interleukin-4 (IL-4) 5 or IL-13. 6,7 DCs are then loaded with tumor antigens, matured, and reinjected into patients. Different protocols have been proposed to load DCs with tumor antigens; the most common forms of antigen are preprocessed peptides, tumor cell lysates, whole apoptotic cells, and necrotic tumor cells (for a review, see Schuler et al 8 ). Numerous in vivo and in vitro assays have been used to compare the capacities of DCs loaded with the different forms of antigen to activate naive T cells. [9][10][11][12][13][14] Antigen loading using whole apoptotic or necrotic tumoral cells and cell lysates allows the presentation of an entire set of tumor antigens by major histocompatibility complex (MHC) class I and class II molecules, 15-17 which seems advantageous for recruiting large CD4 and CD8 T-cell repertoires. 18 Moreover, the activation of CD4 T cells appears essential because it has been shown that CD8 activation without CD4 help may tolerize CD8 T cells 19 and preclude the establishment of CD8 memory T cells. 20 Indeed, the CD40/CD40L signalization pathway, probably engaged by CD4 cells, is needed to induce full DC maturation and effective activation of CD8 T cells. 21 Immature DCs can internalize apoptotic bodies through multiple mechanisms, among which the recognition of altered self by CD36, 22 integrins ␣v␤3 and ␣v␤5, 23 phosphatidylserine receptor, and the molecular complex iC3b/C1q/ Calreticulin/CD91 24 play crucial roles (for a review, see Savill et al 25 ). These various receptors can mediate intracellular signaling events, thereby modifying DC responses to inflammation stimuli and influencing their migration properties 24 and their antigenpresentation capacity. 26 It is generally accepted that reinjected DCs loaded with tumor antigens must have the capacity to migrate to lymph nodes (LNs), encounter naive T cells, and activate them toward a T H 1 phenotype 8,18 to induce efficient antitumoral cytotoxic responses. This dual ability of DCs to migrate toward secondary lymphoid organs and to orient the immune response is, in our opinion, an important criterion for the design of DC-based vaccines. DC maturation agents such as tumor necrosis factor-␣ (TNF-␣), lipopolysaccharide (LPS), and CD40L have been used to confer these functional attributes to DC preparati...

Lipopolysaccharide‐primed heterotolerant dendritic cells suppress experimental autoimmune uveoretinitis by multiple mechanisms

“…However, phenotypic characterization alone is insufficient to determine whether DC will induce tolerance or immunity 21, 22. In addition, it has been suggested that irrespective of the desired therapeutic outcome (induction of tolerance for prevention of autoimmune disease or immunity for treatment of cancer) DC activation is essential for the effectiveness of immunotherapy as activated DC preferentially migrate from the peripheral tissues into the draining lymph nodes where antigen‐specific interaction with T cells occurs 23, 24, 25…”

Host-Cell Survival and Death During Chlamydia Infection

“…However, it also appears likely that infected cells dying during the course of infection may release both antigen and cellular debris, which could then be taken up by DC and used, together with either bacterial or cellular danger signals [153][154][155], to initiate a T cell response. Although DC can phagocytose chlamydiae and present chlamydial antigens to T cells [156,157], antigens provided by dying cells might be more readily accessible, as apoptotic cells are also transported along the lymphatic vessels and can be processed in lymph nodes [144,158].…”

A Comparative Analysis of Serum and Serum-free Media for Generation of Clinical Grade DCs

“…2,8,9 DCs undergo a differentiation process during which they acquire antigens, migrate to lymphoid tissues and enhance T-cell activation potential. 10 Several stimuli are responsible for DC maturation such as pathogen components or host molecules associated with inflammation. 11 With the increasing development of vaccine strategies to manipulate immunity in a variety of diseases, there is a strong interest in defining protocols and reagents that allow optimal production of DCs from peripheral blood monocytes and define culture conditions that can minimize variability of the cell product.…”