We examine the role of dendritic cells subsets in immunity to peripheral infections, with emphasis on the differences in the regulation of primary and secondary T cell responses to viruses. Our major ...focus is on new developments in the understanding of immunity to infections of the skin and lung, which are crucial entry points for a variety of infectious pathogens. Initially we describe a diverse network of dendritic cell subsets, but then we argue for a more generalized model of reduced complexity.
Tissue-resident memory T (Trm) cells permanently localize to portals of pathogen entry, where they provide immediate protection against reinfection. To enforce tissue retention, Trm cells up-regulate ...CD69 and down-regulate molecules associated with tissue egress; however, a Trm-specific transcriptional regulator has not been identified. Here, we show that the transcription factor Hobit is specifically up-regulated in Trm cells and, together with related Blimp1, mediates the development of Trm cells in skin, gut, liver, and kidney in mice. The Hobit-Blimp1 transcriptional module is also required for other populations of tissue-resident lymphocytes, including natural killer T (NKT) cells and liver-resident NK cells, all of which share a common transcriptional program. Our results identify Hobit and Blimp1 as central regulators of this universal program that instructs tissue retention in diverse tissue-resident lymphocyte populations.
In recent years, various intervention strategies have reduced malaria morbidity and mortality, but further improvements probably depend upon development of a broadly protective vaccine. To better ...understand immune requirement for protection, we examined liver-stage immunity after vaccination with irradiated sporozoites, an effective though logistically difficult vaccine. We identified a population of memory CD8+ T cells that expressed the gene signature of tissue-resident memory T (Trm) cells and remained permanently within the liver, where they patrolled the sinusoids. Exploring the requirements for liver Trm cell induction, we showed that by combining dendritic cell-targeted priming with liver inflammation and antigen recognition on hepatocytes, high frequencies of Trm cells could be induced and these cells were essential for protection against malaria sporozoite challenge. Our study highlights the immune potential of liver Trm cells and provides approaches for their selective transfer, expansion, or depletion, which may be harnessed to control liver infections or autoimmunity.
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•CD8+ tissue-resident memory T cells (Trm cells) can be found in the murine liver•These liver Trm cells survey the liver from within the sinusoids•A prime-and-trap vaccination strategy efficiently induces liver Trm cells•Liver Trm cells are essential for protection against liver-stage malaria after vaccination
While various intervention strategies have reduced morbidity and mortality from malaria, further improvement is likely to depend on an effective vaccine. Fernandez-Ruiz et al. identify liver-resident memory CD8+ T cells as vital for liver-stage immunity and describe a protective vaccination strategy that drives their formation.
Although memory T cells within barrier tissues can persist as permanent residents, at least some exchange with blood. The extent to which this occurs is unclear. Here we show that memory CD4(+) T ...cells in mouse skin are in equilibrium with the circulation at steady state. These cells are dispersed throughout the inter-follicular regions of the dermis and form clusters with antigen presenting cells around hair follicles. After infection or administration of a contact sensitizing agent, there is a sustained increase in skin CD4(+) T-cell content, which is confined to the clusters, with a concomitant CCL5-dependent increase in CD4(+) T-cell recruitment. Skin CCL5 is derived from CD11b(+) cells and CD8(+) T cells, with the elimination of the latter decreasing CD4(+) T-cell numbers. These results reveal a complex pattern of tissue-retention and equilibration for CD4(+) memory T cells in skin, which is altered by infection and inflammation history.
Tissue-resident CD8+ memory T (TRM) cells are immune cells that permanently reside at tissue sites where they play an important role in providing rapid protection against reinfection. They are not ...only phenotypically and functionally distinct from their circulating memory counterparts, but also exhibit a unique transcriptional profile. To date, the local tissue signals required for their development and long-term residency are not well understood. So far, the best-characterised tissue-derived signal is transforming growth factor-β (TGF-β), which has been shown to promote the development of these cells within tissues. In this study, we aimed to determine to what extent the transcriptional signatures of TRM cells from multiple tissues reflects TGF-β imprinting. We activated murine CD8+ T cells, stimulated them in vitro by TGF-β, and profiled their transcriptomes using RNA-seq. Upon comparison, we identified a TGF-β-induced signature of differentially expressed genes between TGF-β-stimulated and -unstimulated cells. Next, we linked this in vitro TGF-β-induced signature to a previously identified in vivo TRM-specific gene set and found considerable (>50%) overlap between the two gene sets, thus showing that a substantial part of the TRM signature can be attributed to TGF-β signalling. Finally, gene set enrichment analysis further revealed that the altered gene signature following TGF-β exposure reflected transcriptional signatures found in TRM cells from both epithelial and non-epithelial tissues. In summary, these findings show that TGF-β has a broad footprint in establishing the residency-specific transcriptional profile of TRM cells, which is detectable in TRM cells from diverse tissues. They further suggest that constitutive TGF-β signaling might be involved for their long-term persistence at tissue sites.
Effective immunity is dependent on long-surviving memory T cells. Various memory subsets make distinct contributions to immune protection, especially in peripheral infection. It has been suggested ...that T cells in nonlymphoid tissues are important during local infection, although their relationship with populations in the circulation remains poorly defined. Here we describe a unique memory T cell subset present after acute infection with herpes simplex virus that remained resident in the skin and in latently infected sensory ganglia. These T cells were in disequilibrium with the circulating lymphocyte pool and controlled new infection with this virus. Thus, these cells represent an example of tissue-resident memory T cells that can provide protective immunity at points of pathogen entry.
Tissue-resident memory T cells (T(RM) cells) provide superior protection against infection in extralymphoid tissues. Here we found that CD103(+)CD8(+) T(RM) cells developed in the skin from ...epithelium-infiltrating precursor cells that lacked expression of the effector-cell marker KLRG1. A combination of entry into the epithelium plus local signaling by interleukin 15 (IL-15) and transforming growth factor-β (TGF-β) was required for the formation of these long-lived memory cells. Notably, differentiation into T(RM) cells resulted in the progressive acquisition of a unique transcriptional profile that differed from that of circulating memory cells and other types of T cells that permanently reside in skin epithelium. We provide a comprehensive molecular framework for the local differentiation of a distinct peripheral population of memory cells that forms a first-line immunological defense system in barrier tissues.
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.
This review examines the role of cross-presentation in tolerance and
immunity. We discuss (
a
) the antigenic requirements for
cross-presentation, (
b
) the phenotype of the antigen presenting cell
...(APC), (
c
) the cellular interactions and molecular signals involved in
cross-priming, and (
d
) the factors that direct the immune system toward
tolerance or immunity. A large part of this review is dedicated to summarizing
our current knowledge of the cross-presenting APC.
Although tissue-resident memory T cells (T
cells) are critical in fighting infection, their fate after local pathogen re-encounter is unknown. Here we found that skin T
cells engaged virus-infected ...cells, proliferated in situ in response to local antigen encounter and did not migrate out of the epidermis, where they exclusively reside. As a consequence, secondary T
cells formed from pre-existing T
cells, as well as from precursors recruited from the circulation. Newly recruited antigen-specific or bystander T
cells were generated in the skin without displacement of the pre-existing T
cell pool. Thus, pre-existing skin T
cell populations are not displaced after subsequent infections, which enables multiple T
cell specificities to be stably maintained within the tissue.
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