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• W2895488966 abstract "•TCR stimulation is essential for liver Trm cell formation•Liver Trm cells require IL-15•Local antigen presentation and inflammation enhance liver Trm cell formation•Newly formed liver Trm cells do not displace existing Trm cell populations Liver tissue-resident memory T (Trm) cells migrate throughout the sinusoids and are capable of protecting against malaria sporozoite challenge. To gain an understanding of liver Trm cell development, we examined various conditions for their formation. Although liver Trm cells were found in naive mice, their presence was dictated by antigen specificity and required IL-15. Liver Trm cells also formed after adoptive transfer of in vitro-activated but not naive CD8+ T cells, indicating that activation was essential but that antigen presentation within the liver was not obligatory. These Trm cells patrolled the liver sinusoids with a half-life of 36 days and occupied a large niche that could be added to sequentially without effect on subsequent Trm cell cohorts. Together, our findings indicate that liver Trm cells form as a normal consequence of CD8+ T cell activation during essentially any infection but that inflammatory and antigenic signals preferentially tailor their development. Liver tissue-resident memory T (Trm) cells migrate throughout the sinusoids and are capable of protecting against malaria sporozoite challenge. To gain an understanding of liver Trm cell development, we examined various conditions for their formation. Although liver Trm cells were found in naive mice, their presence was dictated by antigen specificity and required IL-15. Liver Trm cells also formed after adoptive transfer of in vitro-activated but not naive CD8+ T cells, indicating that activation was essential but that antigen presentation within the liver was not obligatory. These Trm cells patrolled the liver sinusoids with a half-life of 36 days and occupied a large niche that could be added to sequentially without effect on subsequent Trm cell cohorts. Together, our findings indicate that liver Trm cells form as a normal consequence of CD8+ T cell activation during essentially any infection but that inflammatory and antigenic signals preferentially tailor their development. Tissue-resident memory T cells are a recently described population of cells that are crucial for defense against pathogens at the site of infection (Schenkel and Masopust, 2014Schenkel J.M. Masopust D. Tissue-resident memory T cells.Immunity. 2014; 41: 886-897Abstract Full Text Full Text PDF PubMed Scopus (609) Google Scholar). As their name suggests, these cells do not recirculate like their effector memory T (Tem) and central memory T (Tcm) cell counterparts but, instead, remain localized within specific tissues (Jiang et al., 2012Jiang X. Clark R.A. Liu L. Wagers A.J. Fuhlbrigge R.C. Kupper T.S. Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity.Nature. 2012; 483: 227-231Crossref PubMed Scopus (629) Google Scholar, Klonowski et al., 2004Klonowski K.D. Williams K.J. Marzo A.L. Blair D.A. Lingenheld E.G. Lefrançois L. Dynamics of blood-borne CD8 memory T cell migration in vivo.Immunity. 2004; 20: 551-562Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar). This is in part due to their reduced expression of the sphingosine 1 phosphate (S1P) receptor (Mackay et al., 2015Mackay L.K. Braun A. Macleod B.L. Collins N. Tebartz C. Bedoui S. Carbone F.R. Gebhardt T. Cutting edge: CD69 interference with sphingosine-1-phosphate receptor function regulates peripheral T cell retention.J. Immunol. 2015; 194: 2059-2063Crossref PubMed Scopus (320) Google Scholar) and CCR7 (Wakim et al., 2012Wakim L.M. Woodward-Davis A. Liu R. Hu Y. Villadangos J. Smyth G. Bevan M.J. The molecular signature of tissue resident memory CD8 T cells isolated from the brain.J. Immunol. 2012; 189: 3462-3471Crossref PubMed Scopus (259) Google Scholar), both of which enable cells to migrate out of peripheral tissues into draining lymph nodes. Trm cells found in all tissues typically express the early activation marker CD69 and often CD103, but these markers do not precisely define Trm cells (Steinert et al., 2015Steinert E.M. Schenkel J.M. Fraser K.A. Beura L.K. Manlove L.S. Igyártó B.Z. Southern P.J. Masopust D. Quantifying Memory CD8 T Cells Reveals Regionalization of Immunosurveillance.Cell. 2015; 161: 737-749Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar). Regardless of their surface profiles, Trm cells found in all tissues express a core gene signature associated with residency, including the expression of Hobit, Ctla4, Cdh1, Cdh2, Cd244, and Xcl1 (Mackay et al., 2013Mackay 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.The developmental pathway for CD103(+)CD8+ tissue-resident memory T cells of skin.Nat. Immunol. 2013; 14: 1294-1301Crossref PubMed Scopus (787) Google Scholar). Protection mediated by Trm cells has been associated with the production of cytokines, such as interferon-γ (IFN-γ) and tumor necrosis factor α (TNF-α), as well as markers of cytotoxicity, such as granzyme B and CD107a (Fernandez-Ruiz et al., 2016Fernandez-Ruiz D. Ng W.Y. Holz L.E. Ma J.Z. Zaid A. Wong Y.C. Lau L.S. Mollard V. Cozijnsen A. Collins N. et al.Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection.Immunity. 2016; 45: 889-902Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar), indicating that these cells are poised to respond to immediate threats. We have recently identified a population of Trm cells within the liver that are critical for protection from Plasmodium infection (malaria) (Fernandez-Ruiz et al., 2016Fernandez-Ruiz D. Ng W.Y. Holz L.E. Ma J.Z. Zaid A. Wong Y.C. Lau L.S. Mollard V. Cozijnsen A. Collins N. et al.Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection.Immunity. 2016; 45: 889-902Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar). Large numbers of Trm cells were found in the liver after vaccination with radiation-attenuated sporozoites (RAS) or after a prime-and-trap vaccination approach, which utilizes priming with antigen targeted to Clec9A on conventional type 1 dendritic cells (cDC1s) combined with “trapping” of Trm cells in the liver upon recognition of hepatocyte-expressed antigen encoded by an adeno-associated viral vector. Trm cells generated by these vaccination strategies expressed high levels of the surface markers CD69, CXCR6, CXCR3, and CD101, but lacked expression of CD62L and KLRG1. Moreover, these Trm cells patrolled the liver sinusoids using a crawling motion that enabled scanning of hepatocytes for cognate antigen. The location of liver Trm cells in the sinusoids, which represent part of the blood stream, distinguishes these cells from most other Trm cells, which are found within parenchyma of peripheral tissues. Although both RAS vaccination and prime-and-trap vaccination provided protection against malaria, depletion of liver Trm cells from vaccinated mice by anti-CXCR3 antibody treatment abrogated protection, indicating an essential role of liver Trm cells in vaccine-mediated protection (Fernandez-Ruiz et al., 2016Fernandez-Ruiz D. Ng W.Y. Holz L.E. Ma J.Z. Zaid A. Wong Y.C. Lau L.S. Mollard V. Cozijnsen A. Collins N. et al.Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection.Immunity. 2016; 45: 889-902Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar). We and others have focused on the requirements for generating Trm cells so that maximum numbers can be formed, thereby enhancing immunity. In this study, we investigated the “spontaneous” formation of liver Trm cells in naive mice as well as the role of T cell activation in the establishment of liver Trm cell populations. We also investigated the size of the Trm cell niche in the liver by successively transferring different T cell populations intravenously to seed the liver. Our results show that we can expand the Trm cell population in the liver over 10-fold without altering the number of endogenous Trm cells. Combined, these data show that liver Trm cells develop naturally during the course of an immune response following T cell receptor (TCR) stimulation but that their numbers can be enhanced by liver infection or inflammation. As we previously reported (Fernandez-Ruiz et al., 2016Fernandez-Ruiz D. Ng W.Y. Holz L.E. Ma J.Z. Zaid A. Wong Y.C. Lau L.S. Mollard V. Cozijnsen A. Collins N. et al.Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection.Immunity. 2016; 45: 889-902Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar), Trm cells (CD44highCD62L−CD69+) can be identified in the livers of naive B6 mice (Figures 1A and 1C ), raising the question of whether this memory population forms spontaneously or requires antigenic stimulation. To begin to address this question, we tested for the presence of Trm cells in the livers of naive TCR transgenic mice that had not been exposed to their specific antigen. PbT-I TCR transgenic mice, which express the Vα8.3+ Vβ10+ TCR specific for a Kb-restricted malaria antigen (Lau et al., 2014Lau L.S. Fernandez-Ruiz D. Mollard V. Sturm A. Neller M.A. Cozijnsen A. Gregory J.L. Davey G.M. Jones C.M. Lin Y.H. et al.CD8+ T cells from a novel T cell receptor transgenic mouse induce liver-stage immunity that can be boosted by blood-stage infection in rodent malaria.PLoS Pathog. 2014; 10: e1004135Crossref PubMed Scopus (57) Google Scholar), were shown to contain both naive (CD44low) and memory (CD44high) CD8+ T cell populations in their spleens and livers, with significant numbers of Trm cells in the liver (Figures 1A–1C). Such liver Trm cells in PbT-I transgenic mice expressed the Vα and Vβ chains of the transgenic TCR, as did similar Trm cell populations in several other TCR transgenic lines (i.e., OT-I, gBT-I, and P14), although the frequency and number of these cells varied between lines (Figure S1). This supported the possibility that liver Trm cells were able to form in the absence of antigenic stimulation, although the potential for activation through co-expressed recombined endogenous TCR in these lines hampered this conclusion. It was also noted that small numbers of T cells found in the spleen were detected as CD44highCD62L−CD69+ (Figures 1A and 1B). Although splenic Trm cells have been reported previously (Schenkel et al., 2014Schenkel J.M. Fraser K.A. Masopust D. Cutting edge: resident memory CD8 T cells occupy frontline niches in secondary lymphoid organs.J. Immunol. 2014; 192: 2961-2964Crossref PubMed Scopus (143) Google Scholar), it was unclear whether the small population detected here were legitimate splenic Trm cells or simply background staining artifacts. Because these cells were not the focus of our study, we will cautiously refer to them as splenic Trm cells for the remainder of the paper but acknowledge that this is not definitive. One trivial explanation for the presence of cells with a liver Trm cell phenotype (CD44highCD62L−CD69+) in PbT-I mice (and other TCR transgenic lines) was that these cells were related to liver-resident natural killer T (NKT) cells, mucosal associated invariant T (MAIT) cells, or other unconventional T cells that had been forced to express the transgenic TCR. However, this did not appear to be the case because Trm cells found in PbT-I mice lacked expression of the transcription factor promyelocytic leukemia zinc finger (PLZF) (Figure 1D), confirming that they were different from NKT cells and MAIT cells. Consistent with the presence of legitimate liver Trm cells in naive PbT-I mice, these mice were resistant to infection by P. berghei sporozoites (Figure 1E), which has been shown to depend on liver Trm cells (Fernandez-Ruiz et al., 2016Fernandez-Ruiz D. Ng W.Y. Holz L.E. Ma J.Z. Zaid A. Wong Y.C. Lau L.S. Mollard V. Cozijnsen A. Collins N. et al.Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection.Immunity. 2016; 45: 889-902Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar). Identification of bona fide liver Trm cells in PbT-I TCR transgenic mice raised the unlikely possibility that these cells formed spontaneously from a naive repertoire. An alternative explanation, however, was that their formation depended on co-expression of endogenously rearranged TCRs that enabled antigen-mediated activation and/or recruitment to the liver. To explore this possibility, we examined liver Trm cell formation in a second TCR transgenic mouse line, Des-TCR, which was specific for allogeneic Kb. These mice were available as either RAG-1-sufficient (termed Des-TCR) or RAG-1-deficient (termed Des-RAG), with the latter unable to rearrange endogenous receptors. Analysis of the spleens of these mice revealed that RAG-1-deficient mice contained very few CD44high memory T cells (Figures 1F–1H). Examination of memory T cell populations within the liver showed that Trm cells were only present in Des-TCR mice when endogenous receptor rearrangement was enabled (Figures 1G and 1I). A requirement for endogenous receptor rearrangement implied that antigen-specific responses to environmental antigens were required for formation of liver Trm cells, arguing against their spontaneous formation from naive T cells. To explore the requirements for environmental antigen-triggered liver Trm cell formation in normal B6 mice, we screened various gene knockout mice for factors potentially important in liver Trm cell homeostasis. This analysis identified interleukin-15 (IL-15) as essential for the presence of liver Trm cells and also showed a minor effect of IFN-γ (Figure 2A). Cytokines such as tumor necrosis factor (TNF) and type I IFN had no significant effect on Trm cell formation, and lack of an effect in Stat6-deficient mice also implied that IL-4 signaling was not essential. These data suggested that endogenous liver Trm cells possessed a typical memory CD8+ T cell requirement for IL-15 but did not exclude a role for this cytokine in their development. Their requirement for IL-15 is explored further below. Although antigen recognition appeared to be essential for constitutive formation of liver Trm cells, it was unclear whether this was simply required to activate T cells or as an antigen recognition step within the liver. To address this issue, we asked whether in vitro-activated TCR transgenic T cells could form liver Trm cells independent of antigen recognition within the liver. Ly5.1+ ovalbumin (OVA)-specific TCR transgenic MHC I-restricted (OT-I) CD8+ T cells (RAG-sufficient background) were activated with peptide in vitro and then transferred into naive B6 mice to assess liver Trm cell formation. After 2 weeks, livers and spleens were removed and examined for the presence of memory OT-I T cells based on expression of Ly5.1, CD44, CD62L, and CD69 (Figure 2B). This revealed formation of OT-I Trm cells (CD44highCD62L−CD69+) in the livers of recipient mice, with the spleen containing predominantly Tem cells (CD44highCD62L−CD69−) and Tcm cells (CD44+CD62L+CD69−) (Figures 2B-E). By contrast, transferring naive OT-I T cells into naive B6 mice did not result in the formation of significant numbers of Trm cells. In fact, very few cells could be found in either the liver or spleen 2 weeks after this transfer (Figures 2D and 2E). Our in vitro cultures used peptide, lipopolysaccharide (LPS), and IL-2 to generate large numbers of rapidly proliferating activated T cells for transfer. To test whether Trm cells could be generated in the absence of LPS and IL-2, we compared various activation conditions (Figure S2). OT-I T cells were activated under either neutral conditions (peptide alone or peptide + IL-15) or more inflammatory conditions (LPS with either IL-2 or IL-15). Liver Trm could be generated under all conditions, with the highest proportion generated by peptide alone (Figure S2A). Absolute Trm numbers, however, were highest in the livers of recipient mice receiving OT-I T cells activated in the presence of LPS (Figure S2B), as were total OT-I cell numbers in the spleen (Figure S2C). Thus, liver Trm cells formed irrespective of activation conditions, although the conditions that generated the most circulating memory cells also generated the largest number of liver Trm cells. The ability to generate liver Trm cells from adoptively transferred in vitro-activated T cells allowed us to further explore the role of IL-15 in generating liver Trm cells. To assess this point, in vitro-activated OT-I cells were transferred into B6 or IL-15 knockout mice, and then liver Trm cell formation was measured 2 weeks later (Figure 2F). This showed that liver Trm cell formation was highly dependent on IL-15. Combined, these findings suggested that liver Trm cells formed naturally from activated T cells in the presence of IL-15 and that neither antigen presentation in the liver nor inflammation of this tissue were essential for their formation. To determine whether liver Trm cells derived from in vitro-activated T cells patrolled the liver sinusoids in a manner typical of previously reported liver Trm cells (Fernandez-Ruiz et al., 2016Fernandez-Ruiz D. Ng W.Y. Holz L.E. Ma J.Z. Zaid A. Wong Y.C. Lau L.S. Mollard V. Cozijnsen A. Collins N. et al.Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection.Immunity. 2016; 45: 889-902Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar), mice ubiquitously expressing TdTomato were adoptively transferred with activated GFP-expressing OT-I cells and then, after several weeks, their livers were imaged, and cell migration was assessed (Figure 3A; Video S1). OT-I T cells within the liver showed a mean velocity of 8 μm/min (Figure 3B) and appeared to migrate within the liver sinusoids (Figure 3C). There was a mix of migration phenotypes, with about a quarter of the cells displaying the typical patrolling activity of liver Trm cells (Fernandez-Ruiz et al., 2016Fernandez-Ruiz D. Ng W.Y. Holz L.E. Ma J.Z. Zaid A. Wong Y.C. Lau L.S. Mollard V. Cozijnsen A. Collins N. et al.Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection.Immunity. 2016; 45: 889-902Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar). The remaining OT-I T cells were non-patrolling, either rapidly flowing through the sinusoids or static, the latter suggesting temporary trapping within the tight confines of these narrow blood vessels (Figure 3D). The proportion of patrolling cells was similar to the proportion of Trm cells detected by flow cytometry in equivalent mice (Figures 2B and 2C). Because liver Trm cells have been shown to be essential for protection against sporozoite infection (Fernandez-Ruiz et al., 2016Fernandez-Ruiz D. Ng W.Y. Holz L.E. Ma J.Z. Zaid A. Wong Y.C. Lau L.S. Mollard V. Cozijnsen A. Collins N. et al.Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection.Immunity. 2016; 45: 889-902Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar), we assessed whether memory OT-I cells formed by in vitro activation could provide such protection. To achieve this goal, mice containing liver Trm cells, derived from adoptive transfer of activated OT-I cells 3 weeks earlier, were challenged with live OVA-expressing Plasmodium berghei ANKA (PbA) sporozoites, and protection was assessed (Figure 3E). Complete protection against sporozoite challenge suggested that liver Trm cells formed after adoptive transfer were functional. https://www.cell.com/cms/asset/80eb8803-04a4-4403-b2b7-4793812ca950/mmc2.mp4Loading ... Download .mp4 (42.02 MB) Help with .mp4 files Video S1. Memory T Cells in the Livers of Mice that Received Activated OT-I Cells Show Patrolling Activity within the Liver Sinusoids, Related to Figure 320 million in vitro activated GFP-expressing OT-I cells were transferred into naive TdTomato mice that ubiquitously express a membrane form of TdTomato. Mice were then left for 2-4 weeks to allow memory T cell formation before intravital 2 photon imaging of the liver. To determine the lifespan of liver Trm cells, 5 × 106 activated OT-I T cells were adoptively transferred into B6 mice and then left 14 to 100 days before harvesting livers and assessing Trm cell numbers. By plotting Trm cell number on a log scale and fitting a straight line to the data, we calculated a half-life of approximately 36 days, with a 95% confidence interval of 24–59 days (Figure 4A). In earlier studies (Fernandez-Ruiz et al., 2016Fernandez-Ruiz D. Ng W.Y. Holz L.E. Ma J.Z. Zaid A. Wong Y.C. Lau L.S. Mollard V. Cozijnsen A. Collins N. et al.Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection.Immunity. 2016; 45: 889-902Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar), we had measured Trm cell numbers generated by adoptively transferred malaria-specific PbT-I T cells at various times after vaccination with RAS. Although data points were relatively limited, cautioning over-interpretation, plotting these numbers on the same log scale revealed a similar decay rate of 28 days with a 95% confidence interval of 15–61 days (Figure 4A). To gain an understanding of the nature of the liver Trm cell niche, we examined whether consecutive administration of activated T cells (and their subsequent formation of liver Trm cells) would enable seeding of increased numbers of liver Trm cells or whether the newly forming liver Trm cells would displace preexisting resident memory cells. To explore this question, 5 × 106 activated T cells were consecutively administered from three different TCR transgenic donors; i.e., OT-I, gBT-I, and P14, which recognize respective peptides from OVA, Herpes simplex virus type 1 (HSV) glycoprotein B, and lymphocytic choriomeningitis virus (LCMV) glycoprotein. Cells from each line were activated in vitro and then consecutively transferred into B6 hosts at 4-week intervals in the following order: OT-I, gBT-I, and P14. Four weeks after the final transfer, livers were harvested, and Trm cells were enumerated for each TCR transgenic population (Figure 4B). This showed that the number of OT-I Trm cells surviving to 12 weeks post-transfer was relatively small but unaffected by the subsequent introduction of gBT-I cells and then P14 cells. It also showed that the number of gBT-I Trm cells was unaffected by the later administration of P14 cells. Similarly, these data revealed that the endogenous Trm cell numbers were remarkably stable despite addition of up to three different TCR transgenic cohorts. Overall, the total load of Trm cells increased nearly 5-fold in mice given a single type of transgenic T cell compared with those given all 3 consecutive populations. To determine whether transferred cell numbers could be increased further to perhaps eventually fill the niche, we examined the number of liver Trm cells formed 4 weeks after injecting up to 40 × 106 activated T cells (Figure S3). This revealed that liver Trm cell numbers increased with an increasing dose but began to plateau after injection of 20 × 106 activated T cells. Given that 20 × 106 donor cells from a single injection induced the maximum number of Trm cells, we examined competition between the three TCR transgenic T cells cohorts when 20 × 106 activated cells were transferred at 2-week intervals (Figure 4C). Again, no evidence of competition was seen between consecutive populations, revealing a 10-fold increase in total Trm cell numbers in mice given all three populations. Similarly, OT-I Tcm and Tem cell populations were not reduced by addition of new transgenic populations (Figure S4). To explore the potential for T cell competition in the liver niche after vaccination, in vitro-activated gBT-I cells were transferred into B6 mice, followed 3 weeks later by naive OT-I cells. Mice were then immunized with OVA conjugated to an anti-Clec9A antibody and adjuvanted by CpG (Caminschi et al., 2008Caminschi I. Proietto A.I. Ahmet F. Kitsoulis S. Shin Teh J. Lo J.C. Rizzitelli A. Wu L. Vremec D. van Dommelen S.L. et al.The dendritic cell subtype-restricted C-type lectin Clec9A is a target for vaccine enhancement.Blood. 2008; 112: 3264-3273Crossref PubMed Scopus (356) Google Scholar). The generation of OT-I liver Trm cells by immunization did not alter the number of pre-existing gBT-I liver Trm cells (Figure 4D). Combined, these data suggested that the niche available for liver Trm cell formation was relatively large (exceeding 2 million Trm cells per liver) and that consecutive seeding of populations simply added to existing liver Trm cells. The above findings suggested that liver Trm cells would be generated from any CD8+ T cell population activated during the course of an infection. To examine this possibility, we adoptively transferred 50,000 naive PbT-I T cells into B6 mice and then measured memory T cell populations in the spleen and liver after infection with either blood-stage PbA, which does not infect liver cells, or with PbA RAS, which infect hepatocytes. This revealed that both infection conditions induced liver Trm cell formation (Figures 5A and 5B ). However, comparison of the ratio of liver Trm cells to circulating memory T cells (Tcirc; total Tem cells plus Tcm cells from the spleen) showed a bias toward Trm cell formation after RAS infection (Figure 5D). This difference was also reflected in total liver Trm cell numbers, which were also higher after RAS vaccination, despite infected red blood cells (iRBCs) inducing more circulating memory T cells in the spleen (Figure S5). These findings suggested that, although Trm cells can form spontaneously in the liver following TCR stimulation, factors such as antigen and/or inflammation associated with liver infection may influence the extent of their formation. This is consistent with our earlier observation that expression of antigen in the liver favored formation of liver Trm cells after prime-and-trap vaccination (Fernandez-Ruiz et al., 2016Fernandez-Ruiz D. Ng W.Y. Holz L.E. Ma J.Z. Zaid A. Wong Y.C. Lau L.S. Mollard V. Cozijnsen A. Collins N. et al.Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection.Immunity. 2016; 45: 889-902Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar). Because blood-stage infection with P. berghei can cause some liver inflammation, as measured by the release of acute-phase proteins (Ansar et al., 2009Ansar W. Habib S.K. Roy S. Mandal C. Mandal C. Unraveling the C-reactive protein complement-cascade in destruction of red blood cells: potential pathological implications in Plasmodium falciparum malaria.Cell. Physiol. Biochem. 2009; 23: 175-190Crossref PubMed Scopus (15) Google Scholar, Friedman, 1983Friedman M.J. Control of malaria virulence by alpha 1-acid glycoprotein (orosomucoid), an acute-phase (inflammatory) reactant.Proc. Natl. Acad. Sci. USA. 1983; 80: 5421-5424Crossref PubMed Scopus (45) Google Scholar), and inflammation has been shown to help Trm cell formation in various tissues (Fernandez-Ruiz et al., 2016Fernandez-Ruiz D. Ng W.Y. Holz L.E. Ma J.Z. Zaid A. Wong Y.C. Lau L.S. Mollard V. Cozijnsen A. Collins N. et al.Liver-resident memory CD8+ T cells form a front-line defense against malaria liver-stage infection.Immunity. 2016; 45: 889-902Abstract Full Text Full Text PDF PubMed Scopus (256) Google Scholar, Mackay et al., 2012Mackay L.K. Stock A.T. Ma J.Z. Jones C.M. Kent S.J. Mueller S.N. Heath W.R. Carbone F.R. Gebhardt T. Long-lived epithelial immunity by tissue-resident memory T (TRM) cells in the absence of persisting local antigen presentation.Proc. Natl. Acad. Sci. USA. 2012; 109: 7037-7042Crossref PubMed Scopus (425) Google Scholar, Wakim et al., 2010Wakim L.M. Woodward-Davis A. Bevan M.J. Memory T cells persisting within the brain after local infection show functional adaptations to their tissue of residence.Proc. Natl. Acad. Sci. USA. 2010; 107: 17872-17879Crossref PubMed Scopus (402) Google Scholar), this may have contributed to seeding of Trm cells in the liver during blood-stage infection. To investigate whether liver Trm cells would form after an infection not known to cause liver inflammation, we examined Trm cell formation after cutaneous infection with HSV. One million naive TCR transgenic T cells from the HSV-specific gBT-I line were adoptively transferred into B6 mice that were then infected with HSV by skin scarification. Mice were left 60–65 days before measuring memory cell formation in the liver and spleen (Figures 5A–5C). Liver Trm cells clearly formed after HSV infection, but their proportion relative to circulating memory was lower than seen for malaria (Figure 5D). The absolute number of liver Trm cells in this case was comparable to RAS vaccination (Figure S5), although, overall, much greater responses were induced. This may relate to the greater number of naive gBT-I cells used to monitor this response or to differences in the infections. Together, these data implied that liver Trm cells formed even after infections that did not involve the liver but that inflammation and/or antigen may optimize seeding. To examine the role of inflammatory stimuli on the formation of liver Trm cells, B6 mice were adoptively transferred with activated OT-I cells alone or together with an inflammatory stimulus in the form of poly(I:C), a Toll-like receptor (TLR) 3 agonist, or one of two different types of CpG, which are TLR9 agonists. These mice were then left for 3 weeks before harvesting their livers and assessing liver Trm cell nu" @default.
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• W2895488966 title "CD8+ T Cell Activation Leads to Constitutive Formation of Liver Tissue-Resident Memory T Cells that Seed a Large and Flexible Niche in the Liver" @default.
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• W2895488966 doi "https://doi.org/10.1016/j.celrep.2018.08.094" @default.
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