Cell Host & Microbe

Previews accomplished through epidemiological methods that look for altered signs of transmission or virulence in the human population. However, additional genetic and molecular experimental approaches will be needed to be sure that what is happening in the human population is related to changes in viral genetics. Ongoing monitoring of specimens collected for diagnostic purposes should be performed. Virological studies comparing the replication of EBOV isolates with different genetic sequences can also be performed, but this requires biosafety level 4 containment labs. Additionally, assays that recapitulate the major steps in the virus replication cycle are available and can be employed. Collecting specimens from EBOV patients comes with risk and, tragically, four coauthors on the Science paper contracted and succumbed to EBOV disease. Gire and colleagues can be commended for rapidly determining these viral sequences and for publically releasing the data as they became available (Gire et al., 2014). This openness facilitates public health efforts to contain the

epidemic and scientific efforts to understand it. The sequences that have been reported thus far were collected up until mid-June. Therefore, nearly three months of continuing transmission have elapsed with no significant new sequence data made available through public databases. Hopefully, the genetic material collected for diagnostic purposes will also be put to good use to better understand and respond to the ongoing and tragic epidemic.

J. Med. Published online April 16, 2014. http://dx. doi.org/10.1056/NEJMoa1404505.

ACKNOWLEDGMENTS

Gire, S.K., Goba, A., Andersen, K.G., Sealfon, R.S., Park, D.J., Kanneh, L., Jalloh, S., Momoh, M., Fullah, M., Dudas, G., et al. (2014). Science 345, 1369–1372.

The author thanks Christine Schwall for critical reading of the manuscript and the National Institutes of Health (R01AI05953, U19AI109945, and U19AI109664) and the Department of the Defense, Defense Threat Reduction Agency (HDTRA1-12-10051 and HDTRA1-14-1-0013) for financial support. The content of the information does not necessarily reflect the position or the policy of the federal government, and no official endorsement should be inferred. REFERENCES Baize, S., Pannetier, D., Oestereich, L., Rieger, T., Koivogui, L., Magassouba, N., Soropogui, B., Sow, M.S., Keita, S., De Clerck, H., et al. (2014). N. Engl.

Basler, C.F., and Amarasinghe, G.K. (2009). J. Interferon Cytokine Res. 29, 511–520. Bray, M., Davis, K., Geisbert, T., Schmaljohn, C., and Huggins, J. (1998). J. Infect. Dis. 178, 651–661. Carroll, S.A., Towner, J.S., Sealy, T.K., McMullan, L.K., Khristova, M.L., Burt, F.J., Swanepoel, R., Rollin, P.E., and Nichol, S.T. (2013). J. Virol. 87, 2608–2616. Ebihara, H., Takada, A., Kobasa, D., Jones, S., Neumann, G., Theriault, S., Bray, M., Feldmann, H., and Kawaoka, Y. (2006). PLoS Pathog. 2, e73.

Mateo, M., Carbonnelle, C., Reynard, O., Kolesnikova, L., Nemirov, K., Page, A., Volchkova, V.A., and Volchkov, V.E. (2011). J. Infect. Dis. 204 (Suppl 3 ), S1011–S1020. Mu¨hlberger, E. (2007). Future Virol 2, 205–215. Shabman, R.S., Hoenen, T., Groseth, A., Jabado, O., Binning, J.M., Amarasinghe, G.K., Feldmann, H., and Basler, C.F. (2013). PLoS Pathog. 9, e1003147. Volchkov, V.E., Chepurnov, A.A., Volchkova, V.A., Ternovoj, V.A., and Klenk, H.D. (2000). Virology 277, 147–155.

Instructing the Instructor: Tissue-Resident T Cells Activate Innate Immunity Bram Slu¨tter1 and John T. Harty1,2,3,* 1Department

of Microbiology Graduate Program in Immunology 3Department of Pathology University of Iowa, Iowa City, IA 52242, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.chom.2014.09.011 2Interdisciplinary

A small number of tissue-resident memory T cells (Trm) provide potent protection against infections. Three recent studies by Ariotti et al. (2014), Schenkel et al. (2014a), and Iijima and Iwasaki (2014) report that Trm rapidly produce cytokines after infection and initiate a tissue-wide anti-viral state by instructing innate immune cells. Cells of the innate immune system such as macrophages, neutrophils, and dendritic cells rapidly respond to infection by phagocytosing and destroying microbes. Additionally, these cells are capable of initiating a tissue-wide inflam-

matory/anti-microbial state when they sense danger through their pattern recognition receptors (PRRs). PRRs are not specific for a particular pathogen antigen but recognize common microbial traits (e.g., LPS from gram negative bac-

teria, unmethylated CpG DNA from bacteria and DNA viruses). T cells, on the other hand, can provide a very specific response through their clonal T cell receptors and are pivotal in the elimination intracellular pathogens. However, naı¨ve

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Previews Trm

DC

TNF-α IL-2 IFN-γ

NK

M

VCAM-1

B-cell Figure 1. Trm Are Maintained through a Network of Local Macrophages and Initiate a Local Anti-Viral State upon Re-Infection When an epithelium is re-infected, Trm can quickly detect infected epithelial cells (red) and respond by producing cytokines. These cytokines induce a tissue wide anti-viral state (blue). Moreover, Trm-derived IFN-g promotes additional lymphocyte recruitment by inducing upregulation of the adhesion molecule VCAM-1, TNF-a promotes DC maturation, and IL-2 induces activation of NK cells. During steady state, Trm may produce a low level of IFN-g that does not induce an anti-viral state but is sufficient to induce CCL5 production by local macrophages. CCL5 in turn may prevent shedding of Trm into the lumen.

antigen-specific T cells rely on the innate immune system for proper instruction, as these cells are relatively infrequent and cannot enter most non-lymphoid tissues. Naı¨ve T cell activation is instructed by interactions with mature dendritic cells expressing cognate antigens in the context of MHCI or MCHII molecules with additional information provided by costimulatory interactions and inflammatory cytokines. Upon integration of these specific instructions, T cells greatly expand in number and acquire the capacity to infiltrate infected tissues. Most of these T cells will die by apoptosis after the infection is cleared; however, some will persist as memory T cells and spread throughout the circulation. In recent years it has become evident that a subset of these memory T cells can stay behind in the previously infected tissue. These memory cells are referred to as tissue-resident memory T cells (Trm) and are found at many sites that are prone to reinfection (skin, lung, intestine, and reproductive tract). Systemic depletion experiments have shown that Trm do not circulate and are maintained independently of the circulating memory T cell population. Importantly, various reports using parabiotic mice show that Trm’s proximity to the site of infection allows superior protection to homologous infection compared to circulating memory T cells. How a small number of Trm provide such potent protection, however, has remained unclear. In a recent issue of Science, three groups independently report that Trm can turn the tables and rapidly become in-

structors of the innate immune system. Ariotti et al. (2014) report that herpes simplex virus 1 (HSV-1)-specific CD8+ Trm in the skin rapidly initiate a local anti-viral state after infection with HSV-1. In mice containing Trm, an upregulation of genes involved in inflammation and innate immunity was observed as early as 3 hr post infection, which was not observed in skin devoid of Trm or that contained Trm that were unable to produce IFN-g. Schenkel et al. (2014a) found that CD8+ Trm in the murine female reproductive tract produce IFN-g, TNF-a, and IL-2 within 12 hr after vaginal vaccinia infection. These cytokines have distinct functions in initiating an anti-viral state in the female reproductive tract (Figure 1). Trm-derived IFN-g drives the expression of the adhesion molecule VCAM-1 on endothelial cells in the reproductive tract and mediates concurrent recruitment of B cells. TNF-a induces dendritic cell maturation and IL-2 activates NK-cells. Finally, Iijima and Iwasaki (2014) show that not only CD8 Trm but also CD4 Trm rapidly produce IFN-g and mediate protection against HSV-2 infection in the genital mucosa. These findings suggest that Trm can act as pathogen-specific sentinels in the periphery, making these cells conceptually similar to innate cells that use PRR to detect infection. Their proximity to newly infected cells and their propensity to produce proinflammatory cytokines allows Trm to rapidly initiate an innate immune response in the infected tissue. The idea that a small number of antigen-specific T cells in the right place can provide protection without the need

422 Cell Host & Microbe 16, October 8, 2014 ª2014 Elsevier Inc.

for a large systemic memory T cell population is enticing with regard to vaccine development, as the generation of large memory T cell populations in humans has often proven difficult. How best to generate and maintain Trm remains unclear as these populations are only observed after local infection. For instance, vaccinia virus administration through skin scarification results in a Trm population in the epidermis, which is not observed with vaccinia virus administered through a systemic route (Jiang et al., 2012). Recent studies suggest that responding T cells receive signals in the local microenvironment that permit adoption of a phenotype compatible with that particular tissue (Wakim et al., 2010). Microarray studies indeed show various transcriptional differences between circulating memory T cells and Trm but also between Trm from different tissues (Mackay et al., 2013), suggesting the signals Trm receive are different for every tissue. Despite these differences, some commonalities can be observed. A pivotal transformation for Trm is downregulation of the transcription factor KLF-2 and expression of the transmembrane C-type lectin CD69 (Skon et al., 2013). CD69 inhibits S1P receptor signaling that controls T cell migration and thus prevents Trm from exiting the tissue. Cytokines that are abundant in infected tissue including TGF-b, TNF-a, and IL-33 can sustain KLF-2 downregulation and thus sustain Trm (Skon et al., 2013). However, it is unknown whether all effector T cells are susceptible to Trm transformation, as some studies suggest terminally differentiated effector (KLRG1+) CD8 T cells do not become Trm (Mackay et al., 2013). TGF-b is constitutively expressed in most tissues and thus may be a key cytokine in the long-term maintenance of Trm. TGF-b is also the driving force behind another key adaptation of Trm, expression of aE integrin (CD103). aE integrin can form a heterodimer with b7 integrin and act a ligand for E-cadherin. As E-cadherin is expressed in various epithelia, expression of CD103 may aid permanent residency of Trm in the epithelium. In that respect, it is interesting that a recently described lymphoid Trm population does not express CD103 (Schenkel et al., 2014b). As an alternative hypothesis, Iijima and Iwasaki (2014) suggest that a local network of macrophages

Cell Host & Microbe

Previews sustains Trm. Depletion of cells expressing CD11b+, a marker for macrophages, led to a reduction in CD4+ (and CD8+) Trm as did blockade of the chemokine CCL5. Moreover, Iijima and Iwaski detected CD4+ Trm that produce a low level of IFN-g ex vivo without the need for restimulation with peptide. They propose a model where Trm-derived-IFN-g induces local macrophages to produce CCL5, which in turn prevents Trm from being expulsed into the vaginal lumen (Figure 1). Thus, Trm not only instruct innate immune cells upon infection but keep instructing them in order to maintain themselves at the initial site of infection. These three recent reports (Ariotti et al., 2014; Iijima and Iwasaki, 2014; Schenkel et al., 2014a) show the potential power and precision Trm may provide to protect against specific infections. In order to translate these findings into effective vaccine strategies, we will need a more comprehensive understanding of how to maximize the number of Trm and to prolong their longevity in a specific tissue. The complexity of Trm is substantial as

CD4+ and CD8+ T cells behave differently and the maintenance of Trm is very tissue specific. For instance, it is unlikely that expulsion into the lumen is a major concern for skin Trm, whereas the large surface area of the lung may require active repression of Trm shedding into the lung airways. On that note, the longevity of Trm appears to greatly differ between tissues as skin Trm are maintained in mice for over a year (Mackay et al., 2012), whereas lung Trm may only be detectable for a few months (Wu et al., 2013). Despite these challenges, vaccine-induced Trm could be worth the effort, particularly in the case of pathogens such as HIV, where rapid induction of an antiviral state by Trm could be pivotal to prevent systemic dissemination.

Iijima, N., and Iwasaki, A. (2014). Science. Published online August 28, 2014. http://dx.doi.org/ 10.1126/science.1257530. Jiang, X., Clark, R.A., Liu, L., Wagers, A.J., Fuhlbrigge, R.C., and Kupper, T.S. (2012). Nature 483, 227–231. Mackay, L.K., Rahimpour, A., Ma, J.Z., Collins, N., Stock, A.T., Hafon, M.L., Vega-Ramos, J., Lauzurica, P., Mueller, S.N., Stefanovic, T., et al. (2013). Nat. Immunol. 14, 1294–1301. Mackay, L.K., Stock, A.T., Ma, J.Z., Jones, C.M., Kent, S.J., Mueller, S.N., Heath, W.R., Carbone, F.R., and Gebhardt, T. (2012). Proc. Natl. Acad. Sci. USA 109, 7037–7042. Schenkel, J.M., Fraser, K.A., Beura, L.K., Pauken, K.E., Vezys, V., and Masopust, D. (2014a). Science. Published online August 28, 2014. http:// dx.doi.org/10.1126/science.1254536. Schenkel, J.M., Fraser, K.A., and Masopust, D. (2014b). J. Immunol. 192, 2961–2964. Skon, C.N., Lee, J.Y., Anderson, K.G., Masopust, D., Hogquist, K.A., and Jameson, S.C. (2013). Nat. Immunol. 14, 1285–1293.

REFERENCES Ariotti, S., Hogenbirk, M.A., Dijkgraaf, F.E., Visser, L.L., Hoekstra, M.E., Song, J., Jacobs, H., Haanen, J.B., and Schumacher, T.N. (2014). Science. Published online August 28, 2014. http://dx.doi.org/10. 1126/science.1254803.

Wakim, L.M., Woodward-Davis, A., and Bevan, M.J. (2010). Proc. Natl. Acad. Sci. USA 107, 17872–17879. Wu, T., Hu, Y., Lee, Y.T., Bouchard, K.R., Benechet, A., Khanna, K., and Cauley, L.S. (2013). J. Leukoc. Biol. 95, 215–224.

Lost but Not Forgotten David Sacks1,* 1Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, MD 20892, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.chom.2014.09.017

During its developmental transformation in the mammalian host, Trypanosma cruzi discards it flagellum into the cytoplasm of the host cell. In the current issue of Cell Host & Microbe, Kurup and Tarleton (2014) exploit the antigens made available by this process to develop a more effective vaccine strategy. The Kinetoplastid protozoan parasites that include African trypanosomes, Trypanosma cruzi, and various Leishmania sp. produce a spectrum of human and veterinary diseases that continue to pose enormous public health concerns throughout tropical and subtropical regions. Importantly, there are no effective vaccines against any of these vector-borne diseases. A major impediment to vaccine development is the complexity of the antigens that these eukaryotic pathogens offer as immunologic targets and their

remarkable adaptability to immunologic pressure. Thus, the large genome sizes and proteomes possessed by these parasites may preclude responses to anything but a few immunodominant epitopes encoded by genes that are driven to display extensive allelic or somatic polymorphisms. In the current studies, Kurup and Tarleton (2014) develop a strategy to identify invariant, subdominant, and early antigens targets that can be incorporated into a live, attenuated vaccine to potentiate a protective response.

Trypanosma cruzi is the causative agent of Chagas disease, which is the most prevalent cause of infectious myocarditis in Central and South America. The basic life cycle of Trypanosma cruzi was described by Carlos Chagas over one century ago (Chagas, 1909) and is summarized in Figure 1. Metacyclic trypomastigotes are the flagellated, extracellularstage parasites that are excreted by an infected reduviid bug. The excreta can contaminate the bite wound or mucous membranes, allowing the metacyclics to

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Instructing the instructor: tissue-resident T cells activate innate immunity.

A small number of tissue-resident memory T cells (Trm) provide potent protection against infections. Three recent studies by Ariotti et al. (2014), Sc...
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