Leishmaniasis, contact hypersensitivity and graft‐versus‐host disease: understanding the role of dendritic cell subsets in balancing skin immunity and tolerance

Abstract

Dendritic cells (DC) are key elements of the immune system. In peripheral tissues, they function as sentinels taking up and processing antigens. After migration to the draining lymph nodes, the DC either present antigenic peptides by themselves or transfer them to lymph node-resident DC. The skin is the primary interface between the body and the environment and host's various DC subsets, including dermal DC (dDC) and Langerhans cells (LC). Because of their anatomical position in the epidermis, LC are believed to be responsible for induction of adaptive cutaneous immune responses. The functions of LC and dDC in the skin immune system in vivo are manifold, and it is still discussed controversially whether the differentiation of T-cell subtypes (e.g. effector T cells and regulatory T cells) may be initiated by distinct DC subtypes. As skin DC are able to promote or downmodulate immune responses, we chose different skin diseases (cutaneous leishmaniasis, contact hypersensitivity, UV radiation-induced suppression, and graft-versus-host disease) to describe the biological interactions between different DC subtypes and T cells that lead to the development of efficient or unwanted immune responses. A detailed knowledge about the immune modulatory capacity of different cutaneous DC subsets might be helpful to specifically target these cells through the skin during therapeutic interventions.

Cutting Edge: Virus Selectively Primes Human Langerhans Cells for CD70 Expression Promoting CD8+ T Cell Responses

“…A series of viral infection studies have advocated the general concept that CD8 + T cells are not directly activated by migrating DC subsets, including LCs, but rather by resident DCs that have picked up viral Ag in draining lymphoid tissue (25)(26)(27). However, this concept has been challenged by more recent studies in mouse models of FLU (23,28) and Leishmania (29,30), which provide evidence that migratory DCs, including LCs, are able to directly present Ags to CD8 + T cells. In conclusion, our data provide further insight in the relative roles of epidermal and dermal DCs in the initiation of T cell immunity.…”

TIM-4 is differentially expressed in the distinct subsets of dendritic cells in skin and skin-draining lymph nodes and controls skin Langerhans cell homeostasis

“…The ratios of CD207 + DDCs, CD207 − CD11b − and CD207 − CD11b + DDCs in TIM-4 KO mice were all within normal ranges, and were comparable to that of TIM-4 WT mice (Figure 3b, 3c) [41]. …”

“…The skin-draining LNs contain two major populations of DCs: One subset is migratory DCs, which include epidermal LCs and CD207 + DDCs; the other subpopulation is tissue-resident DCs, which encompass CD207 + CD8 + DCs and a group of conventional CD207 − DCs subcategorized based on the expression of CD4 and CD8 [41–43]. As depicted in Figure 2a, LN mLCs maintained a similar level of TIM-4 expression compared to their dermal counterparts LCs in transit , whereas migrated CD207 + DDCs (CD207 + mDDC) slightly decreased their TIM-4 expression upon migration.…”

IL-10 signaling in dendritic cells attenuates anti- Leishmania major immunity without affecting protective memory responses

“…DCs have the unique capacity to balance skin immunity and tolerance (Kautz-Neu et al, 2010) and are targets of IL-10 both in vitro and in the skin (Girard-Madoux et al, 2012). Moreover, we recently discovered that Langerhans cells, the unique DC population residing in the epidermis, are negative regulators of the anti-Leishmania response, which is in part mediated by IL-10 (Kautz-Neu et al, 2011).…”