Dendritic cells and humoral immunity in humans

Abstract

Dendritic cells (DCs) orchestrate the innate and adaptive immune systems to induce tolerance and immunity. DC plasticity and subsets are prominent determinants in the regulation of immune responses. Our recent studies suggest that humoral and cellular immunity is regulated by different myeloid DC subsets with distinct intrinsic properties in humans. Although antibody response is preferentially mediated by CD14(+) dermal DCs, cytotoxic T-cell response is preferentially mediated by Langerhans cells (LCs). Thus, mechanisms whereby DCs induce humoral and cellular immunity seem to be fundamentally distinct. In this review, we will focus on the role of DCs in the development of humoral immunity. We will also discuss the mechanisms whereby DCs induce CD4(+) T cells associated with aiding B-cell response, including T follicular helper (Tfh) cells, and why human LCs lack this ability.

Figure 1. CD14⁺ dermal DCs preferentially induce humoral immunity, while Langerhans cells induce cellular immunity

Upon activation, epidermal LCs and CD14⁺ dermal DCs migrate to the secondary lymphoid organs through afferent lymphatics. Dermal DCs migrate into the outer paracortex, just beneath the B cell follicles, whereas LCs migrate into the T cell rich area. LCs are efficient at inducing high avidity-cytotoxic CD8⁺ T cell and Th1, Th2, and Th22 responses. In contrast, CD14⁺ dermal DCs are efficient at inducing the differentiation of naïve B cells into antibody-secreting cells (ASC) and at promoting the development of T follicular helper (Tfh) cells. CD4⁺ T cells primed by LCs might be efficient at helping the development of CTL responses.

Figure 2. Human activated DCs induce IL-21-producing T follicular helper (Tfh)-like cells via IL-12

IL-12 induces human naïve CD4⁺ T cells to differentiate into two different types of IL-21-producing CD4⁺ T cells: IFN-γ⁺IL-21⁺ Th1 cells expressing T-bet, and IFN-γ⁻IL-21⁺ non-Th1 cells. Both IL-21-producing CD4⁺ T cells develop in a manner dependent on STAT4. IL-23 induces only IFN-γ⁻IL-21⁺ non-Th1 cells through STAT3. The induction of IFN-γ⁻IL-21⁺ non-Th1 cells by IL-12 appears to be partially dependent on STAT3 as well.

Figure 3. Possible involvement of IL-12 secreted from DCs in the development of antibody responses during DC-T cell-B cell “ménage à trois” complex

When DCs form the complex with T cells and B cells at extrafollicular sites, IL-12 derived from activated DCs promotes B cells to differentiate into antibody-secreting cells (ASCs) by two different paths: a direct path via DC-B interaction, and an indirect path through induction of IL-21-producing helper cells.