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high pDCs secrete higher levels of IL12p40, express higher levels of costimulatory molecule CD80, and are more efficient in triggering proliferation of naive allogeneic T cells. Thus, human blood pDCs are composed of subsets with specific phenotype and functions.

Owing to their properties, dendritic cells (DCs) are often called 'nature's adjuvants' and thus have become the natural targets for antigen delivery. DCs provide an essential link between the innate and the adaptive immune responses. DCs are at the center of the immune system owing to their ability to control both tolerance and immunity. DCs are thus key targets for both preventive and therapeutic vaccination. Herein, we will discuss recent progresses in our understanding of DC subsets physiology as it applies to vaccination.Dendritic cells (DCs) are key regulators of innate and adaptive immune responses [1,2]. The plasticity of DCs in response to extrinsic signals and the existence of distinct DC subsets with distinct functions contribute to the mounting of highly diverse immune responses. DCs are essential in pathogen resistance including different viruses, bacteria and parasites as demonstrated using DC-depleted mice [3]. Vaccine adjuvants primarily act via activation of DCs. Preventive vaccines are designed to initiate protective humoral immune responses. Today, more than 70 preventive vaccines have been licensed for use against approximately 30 microbes, sparing countless lives [4 •• ]. However, effective vaccines remain elusive for diseases such as human immunodeficiency virus (HIV)-induced acquired immune deficiency syndrome, plasmodium-induced malaria, virus-induced hepatitis C, and Mycobacterium-induced tuberculosis, to cite a few [4 •• ]. Most of these are chronic diseases for which it is thought that strong cellular immunity, in particular cytotoxic T cells, is necessary to eliminate the cells that are infected with the causative agent. Therapeutic vaccines have been designed to eliminate existing diseases and cancer represents an important target for such therapeutic vaccines. Early studies also indicate that vaccines might also be developed in noninfectious settings for the treatment of allergy, and autoimmunity. Here we will discuss recent insights and current views on the biology of human DC subsets in the context of vaccination. Human DC subsetsWhile there has been considerable progress in understanding the ontogeny of mouse DC subsets [5,6], less is known on the origin of human DCs and their differentiation program. This is due to their rarity in the blood, the poor accessibility of human tissues and the limited experimental approaches that can be applied to humans. Care should be taken, however, in extending the data generated from mouse DC subsets to human DC subsets. The knowledge of human DC subsets came from studies on blood and skin DC subsets. These studies have distinguished human-blood-circulating DC subsets based on three main cell surface markers: CD303 (BDCA-2) on plasmacytoid DCs (pDCs), CD1c (or BDCA-1) expressed on the majority of circulating DCs and CD141 (or BDCA-3) expressed on a minute population [7][8][9]. Human CD141 + CD1c − DCs uniquely express Toll like receptor 3; produce IL-12 and Corresponding authors: Palucka, Karolina (karolinp@baylorhealth.edu) and Bancherea...

Common variable immunodeficiency (CVID) is a very heterogeneous syndrome defined by impaired immunoglobulin production. The functional classification of CVID patients on the basis of in vitro immunoglobulin production is time consuming and has never shown any predictive value. We propose a classification based on the quantitative repartition of naive/memory B cells according to the dual expression of IgD and CD27. Fifty-seven patients were categorized into three groups: Group MB2 (11 patients, 19%) with normal memory B cells; Group MB1 (19 patients, 33%) with defective switched memory (IgD-CD27+) but normal nonswitched memory B cells (IgD+CD27+); Group MB0 (27 patients, 47%) with almost no memory B cells. In addition, a downexpression of activation markers (CD25, CD21, CD80, CD86) on B cells characterized the group MB1 patients and was associated with an upexpression of activation markers (HLA-DR, CD95, CD57) on T cells. This classification correlates with some clinical aspects showing a higher prevalence of splenomegaly (16/27, 59%), lymphoid proliferation (13/27, 48%) and granulomatous disease (12/27, 44%) in group MB0. Splenomegaly was also frequent in group MB1 (8/19, 42%). In contrast, autoimmunity was observed with similar prevalence in all three groups. Moreover, by analyzing B cell phenotype, immunoglobulin transcript expression, and somatic mutations, we propose different putative mechanisms responsible for impaired B cell activation and memory differentiation in this syndrome.