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Barrier tissues such as the skin contain various populations of immune cells that contribute to protection from infections. These include recently identified tissue-resident memory T cells (T RM). In the skin, these memory CD8 ⁺ T cells reside in the epidermis after being recruited to this site by infection or inflammation. In this study, we demonstrate prolonged persistence of epidermal T RM preferentially at the site of prior infection despite sustained migration. Computational simulation of T RM migration within the skin over long periods revealed that the slow rate of random migration effectively constrains these memory cells within the region of skin in which they form. Notably, formation of T RM involved a concomitant local reduction in dendritic epidermal γδ T-cell numbers in the epidermis, indicating that these populations persist in mutual exclusion and may compete for local survival signals. Accordingly, we show that expression of the aryl hydrocarbon receptor, a transcription factor important for dendritic epidermal γδ T-cell maintenance in skin, also contributes to the persistence of skin T RM. Together, these data suggest that skin tissue-resident memory T cells persist within a tightly regulated epidermal T-cell niche.

Although circulating memory T cells provide enhanced protection against pathogen challenge, they often fail to do so if infection is localized to peripheral or extralymphoid compartments. In those cases, it is T cells already resident at the site of virus challenge that offer superior immune protection. These tissue-resident memory T (TRM) cells are identified by their expression of the α-chain from the integrin αE(CD103)β7, and can exist in disequilibrium with the blood, remaining in the local environment long after peripheral infections subside. In this study, we demonstrate that long-lived intraepithelial CD103+CD8+ TRM cells can be generated in the absence of in situ antigen recognition. Local inflammation in skin and mucosa alone resulted in enhanced recruitment of effector populations and their conversion to the TRM phenotype. The CD8+ TRM cells lodged in these barrier tissues provided long-lived protection against local challenge with herpes simplex virus in skin and vagina challenge models, and were clearly superior to the circulating memory T-cell cohort. The results demonstrate that peripheral TRM cells can be generated and survive in the absence of local antigen presentation and provide a powerful means of achieving immune protection against peripheral infection.

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. Memory T cells are vital responders to skin inflammation, but cell localization and dynamics of exchange with the bloodstream are not clear. Here the authors use parabiosis and intravital microscopy to show that CD4 + memory T cells equilibrate with the circulation and cluster around hair follicles in response to CCL5-dependent responses to viral infection or contact sensitization.

The functions of individual dendritic cell subsets in the skin are unclear. Heath and colleagues now show that langerin-positive CD103 + dermal dendritic cells are the main migratory subtype able to cross-present antigen. 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.

Vaccination with radiation-attenuated sporozoites (RAS) can provide highly effective protection against malaria in both humans and mice. To extend understanding of malaria immunity and inform the development of future vaccines, we studied the protective response elicited by this vaccine in C57BL/6 mice. We reveal that successive doses of Plasmodium berghei RAS favour the generation of liver CD8 + tissue-resident memory T cells (T RM cells) over circulating memory cells and markedly enhance their longevity. Importantly, RAS immunisation strongly skews the composition of the liver CD8 + T RM compartment towards cells specific for abundant sporozoite antigens, such as thrombospondin-related anonymous protein (TRAP) and circumsporozoite protein (CSP), which become major mediators of protection. The increased prevalence of sporozoite specificities is associated with limited intrahepatic attenuated parasite development and inhibition of naïve T cell responses to all parasite antigens, whether formerly encountered or not, in previously vaccinated mice. This leads to the exclusive expansion of effector T cells formed upon initial immunisation, ultimately reducing the diversity of the liver T RM pool later established. However, stronger responses to less abundant epitopes can be achieved with higher initial doses of RAS. These findings provide novel insights into the mechanisms governing malaria immunity induced by attenuated sporozoite vaccination and highlight the susceptibility of this vaccine to limitations imposed by strain-specific immunity associated with the abundant, yet highly variable sporozoite antigens CSP and TRAP.

While CD4 + T cells are a prerequisite for CD8 + T cell-mediated protection against intracellular hepatotropic pathogens, the mechanisms facilitating the transfer of CD4-help to intrahepatic CD8 + T cells are unknown. Here, we developed an experimental system to investigate cognate CD4 + and CD8 + T cell responses to a model-antigen expressed de novo in hepatocytes and reveal that after initial priming, effector CD4 + and CD8 + T cells migrate into portal tracts and peri-central vein regions of the liver where they cluster with type-1 conventional dendritic cells. These dendritic cells are locally licensed by CD4 + T cells and expand the number of CD8 + T cells in situ, resulting in larger effector and memory CD8 + T cell pools. These findings reveal that CD4 + T cells promote intrahepatic immunity by amplifying the CD8 + T cell response via peripheral licensing of hepatic type-1 conventional dendritic cells and identify intrahepatic perivascular compartments specialized in facilitating effector T cell-dendritic cell interactions. Here, English et al. show that after expanding in lymphoid tissues, CD4 + and CD8 +  T cells recognising hepatic antigens migrate into specialised vascular liver areas where CD4 +  T cells locally license hepatic dendritic cells and further expand CD8 +  T cell numbers.

Synthetic CpG oligonucleotides (ODN) have potent immunostimulatory properties exploited in clinical vaccine trials. How CpG ODN are captured and delivered to the intracellular receptor TLR9, however, has been elusive. Here we show that DEC-205, a multilectin receptor expressed by a variety of cells, is a receptor for CpG ODN. When CpG ODN are used as an adjuvant, mice deficient in DEC-205 have impaired dendritic cell (DC) and B-cell maturation, are unable to make some cytokines such as IL-12, and display suboptimal cytotoxic T-cell responses. We reveal that DEC-205 directly binds class B CpG ODN and enhances their uptake. The CpG-ODN binding function of DEC-205 is conserved between mouse and man, although human DEC-205 preferentially binds a specific class B CpG ODN that has been selected for human clinical trials. Our findings identify an important receptor for class B CpG ODN and reveal a unique function for DEC-205.

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.

Immunity against malaria depends on germinal center (GC)-derived antibody responses that are orchestrated by T follicular helper (TFH) cells. Emerging data show that the regulatory cytokine IL-10 plays an essential role in promoting GC B cell responses during both experimental malaria and virus infections. Here we investigated the cellular source and temporal role of IL-10, and whether IL-10 additionally signals to CD4 T-cells to support anti- Plasmodium humoral immunity. Distinct from reports of virus infection, we found that IL-10 was expressed by conventional, Foxp3-negative effector CD4 T cells and functioned in a B cell-intrinsic manner only during the first 96 hours of Plasmodium infection to support humoral immunity. The critical functions of IL-10 manifested only before the orchestration of GC responses and were primarily localized outside of B cell follicles. Mechanistically, our studies showed that the rapid and transient provision of IL-10 promoted B cell expression of anti-apoptotic factors, MHC class II, CD83, and cell-cell adhesion proteins that are essential for B cell survival and interaction with CD4 T cells. Together, our data reveal temporal features and mechanisms by which IL-10 critically supports humoral immunity during blood-stage Plasmodium infection, information that may be useful for developing new strategies designed to lessen the burden of malaria.

The skin is a highly complex organ and the main body barrier against pathogens and other environmental factors. Heath and Carbone outline many of the innate and adaptive immune cell types associated with the skin. The skin is a highly complex organ interspersed with a variety of smaller organ-like structures and a plethora of cell types that together perform essential functions such as physical sensing, temperature control, barrier maintenance and immunity. In this Review, we outline many of the innate and adaptive immune cell types associated with the skin, focusing on the steady state in mice and men, and include a broad update of dendritic cell function and T cell surveillance.