Skin-derived dendritic cells (DCs) include Langerhans cells, classical dermal DCs and a langerin-positive CD103(+) dermal subset. We examined their involvement in the presentation of skin-associated viral and self antigens. Only the CD103(+) subset efficiently presented antigens of herpes simplex virus type 1 to naive CD8(+) T cells, although all subsets presented these antigens to CD4(+) T cells. This showed that CD103(+) DCs were the migratory subset most efficient at processing viral antigens into the major histocompatibility complex class I pathway, potentially through cross-presentation. This was supported by data showing only CD103(+) DCs efficiently cross-presented skin-derived self antigens. This indicates CD103(+) DCs are the main migratory subtype able to cross-present viral and self antigens, which identifies another level of specialization for skin DCs.

Infections localized to peripheral tissues such as the skin result in the priming of T-cell responses that act to control pathogens. Activated T cells undergo migrational imprinting within the draining lymph nodes, resulting in memory T cells that provide local and systemic protection. Combinations of migrating and resident memory T cells have been implicated in long-term peripheral immunity, especially at the surfaces that form pathogen entry points into the body. However, T-cell immunity consists of separate CD4(+) helper T cells and CD8(+) killer T cells, with distinct effector and memory programming requirements. Whether these subsets also differ in their ability to form a migrating pool involved in peripheral immunosurveillance or a separate resident population responsible for local infection control has not been explored. Here, using mice, we show key differences in the migration and tissue localization of memory CD4(+) and CD8(+) T cells following infection of the skin by herpes simplex virus. On resolution of infection, the skin contained two distinct virus-specific memory subsets; a slow-moving population of sequestered CD8(+) T cells that were resident in the epidermis and confined largely to the original site of infection, and a dynamic population of CD4(+) T cells that trafficked rapidly through the dermis as part of a wider recirculation pattern. Unique homing-molecule expression by recirculating CD4(+) T effector-memory cells mirrored their preferential skin-migratory capacity. Overall, these results identify a complexity in memory T-cell migration, illuminating previously unappreciated differences between the CD4(+) and CD8(+) subsets.

Human histocompatibility leukocyte antigen (HLA)-E is a nonclassical HLA class I molecule, the gene for which is transcribed in most tissues. It has recently been reported that this molecule binds peptides derived from the signal sequence of HLA class I proteins; however, no function for HLA-E has yet been described. We show that natural killer (NK) cells can recognize target cells expressing HLA-E molecules on the cell surface and this interaction results in inhibition of the lytic process. Furthermore, HLA-E recognition is mediated primarily through the CD94/NKG2-A heterodimer, as CD94-specific, but not killer cell inhibitory receptor (KIR)–specific mAbs block HLA-E–mediated protection of target cells. Cell surface HLA-E could be increased by incubation with synthetic peptides corresponding to residues 3–11 from the signal sequences of a number of HLA class I molecules; however, only peptides which contained a Met at position 2 were capable of conferring resistance to NK-mediated lysis, whereas those having Thr at position 2 had no effect. Interestingly, HLA class I molecules previously correlated with CD94/NKG2 recognition all have Met at residue 4 of the signal sequence (position 2 of the HLA-E binding peptide), whereas those which have been reported not to interact with CD94/NKG2 have Thr at this position. Thus, these data show a function for HLA-E and suggest an alternative explanation for the apparent broad reactivity of CD94/NKG2 with HLA class I molecules; that CD94/NKG2 interacts with HLA-E complexed with signal sequence peptides derived from “protective” HLA class I alleles rather than directly interacting with classical HLA class I proteins.

During lung infection with virus, airway-derived dendritic cells (DC)have been thought to be the dominant cell type involved in acquisition, transport, and direct antigen presentation for cytotoxic T lymphocyte priming. Contrary to this view, we have found that both an airway-derived CD8␣ ؊ CD11b ؊ DC subset and distinct CD8␣ ؉ lymph node resident DC can present class I-restricted antigens after lung infection with influenza virus or herpes simplex virus 1. Presentation by a nonairway-derived DC population argues that cytotoxic T lymphocyte priming may involve interplay between different DC subsets, not all of which originate within the site of infection.T lymphocyte ͉ influenza A virus T he classic paradigm of dendritic cell (DC) involvement in T cell responses revolves around a linear progression of events, starting with their capture of antigen in peripheral tissues and followed by migration to draining lymphoid organs and presentation for the purpose of T cell priming (1). There is ample evidence that DC can acquire antigen in peripheral tissues and transport this to draining lymph nodes (LNs). Separate from this, DC are particularly adept at T cell priming, with their expression of an array of molecules required for this event. However, it is becoming increasingly clear that DC represent a heterogeneous population of cells whose diversity lends itself to subset specialization. There is growing evidence that only certain subsets are involved in T cell priming, possibly even in the distinct type of T cell subset that they engage (2-5). Thus, it can no longer be assumed that DC found to have originated from any particular site of infection are automatically the subset directly implicated in T cell stimulation.We recently have used a model of cutaneous infection with herpes simplex virus (HSV) to show that the dominant skin migrating DC population, the Langerhans cells, were not involved directly in cytotoxic T lymphocyte (CTL) priming to this virus (3). Indeed, it seems likely that the actual priming DC, which belonged to the CD8␣ ϩ DC subset, did not originate within the epidermal layer of skin that harbored the infection, although this could not be proven definitively in this case. Given this finding, we sought to examine other routes of infection to determine whether we could find definitive examples where nonmigrating DC were involved in CTL priming. To this end, we have used a combination of lung infection with virus and direct labeling of tissue-resident DC with a fluorescent dye to show that although there is a population of migrating DC capable of class I-restricted presentation of viral antigen, a dominant nonairwayderived CD8␣ ϩ DC subset previously found to be involved in a number of other CTL priming events also was called into play (2-4, 6, 7). ) was used to analyze antigen presentation by mediastinal LN cells that were released by collagenase͞DNase digestion for 20 min followed by a 5-min incubation with 0.099 M EDTA. Some preparations were depleted of cells expressing CD11c, CD11b, CD8␣, CD4, C...