The Experts below are selected from a list of 2571 Experts worldwide ranked by ideXlab platform
Hanspeter Pircher - One of the best experts on this subject based on the ideXlab platform.
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Characterization of a subset of antigen-specific human central memory CD4+ T lymphocytes producing effector cytokines.
European Journal of Immunology, 2020Co-Authors: Muriel Stubbe, Hanspeter Pircher, Nathalie Vanderheyde, Michel Goldman, Arnaud MarchantAbstract:CCR7+ central memory (TCM) CD4+ T cells play a central role in long-term immunological memory. Recent reports indicate that a proportion of CD4+ TCM is able to produce effector cytokines. The phenotype and the role of this subset remain unknown. We characterized cytokine-producing human CD4+ TCM specific for cleared protein and persistent viral Ag. Our results demonstrate that the type of Ag stimulation is a major determinant of CD4+ TCM differentiation. CMV-specific TCM were significantly more differentiated than protein Ag-specific TCM and included higher proportions of IFN-γ-producing cells. The expression of killer cell lectin-like receptor G1 (KLRG1) by protein Ag- and CMV-specific TCM was associated with increased production of effector cytokines. KLRG1+ TCM expressed high levels of CD127, suggesting that they can survive long term under the influence of IL-7. The induction of KLRG1+ TCM may therefore represent an important target of vaccination against pathogens controlled by cellular immune responses. See accompanying commentary: http://dx.doi.org/10.1002/eji.200738044
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expression of il 7rα and KLRG1 defines functionally distinct cd8 t cell populations in humans
European Journal of Immunology, 2019Co-Authors: Ester B M Remmerswaal, Hanspeter Pircher, Pleun Hombrink, Benjamin Nota, Ineke Ten J M Berge, Rene A W Van Lier, Michiel C Van AalderenAbstract:During acute viral infections in mice, IL-7Rα and KLRG1 together are used to distinguish the short-lived effector cells (SLEC; IL-7Rα lo KLRG hi ) from the precursors of persisting memory cells (MPEC; IL-7Rα hi KLRG1 lo ). We here show that these markers can be used to define distinct subsets in the circulation and lymph nodes during the acute phase and in “steady state” in humans. In contrast to the T cells in the circulation, T cells derived from lymph nodes hardly contain any KLRG1-expressing cells. The four populations defined by IL-7Rα and KLRG1 differ markedly in transcription factor, granzyme and chemokine receptor expression. When studying renal transplant recipients experiencing a primary hCMV and EBV infection, we also found that after viral control, during latency, Ki-67-negative SLEC can be found in the peripheral blood in considerable numbers. Thus, combined analyses of IL-7Rα and KLRG1 expression on human herpes virus-specific CD8 + T cells can be used to separate functionally distinct subsets in humans. As a noncycling IL-7Rα lo KLRG1 hi population is abundant in healthy humans, we conclude that this combination of markers not only defines short-lived effector cells during the acute response but also stable effector cells that are formed and remain present during latent herpes infections.
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Expression of IL-7Rα and KLRG1 defines functionally distinct CD8 + T-cell populations in humans
European Journal of Immunology, 2019Co-Authors: Ester B M Remmerswaal, Hanspeter Pircher, Pleun Hombrink, Benjamin Nota, Rene A W Van Lier, Ineke J. M. Ten Berge, Michiel C Van AalderenAbstract:During acute viral infections in mice, IL-7Rα and KLRG1 together are used to distinguish the short-lived effector cells (SLEC; IL-7Rα lo KLRG hi ) from the precursors of persisting memory cells (MPEC; IL-7Rα hi KLRG1 lo ). We here show that these markers can be used to define distinct subsets in the circulation and lymph nodes during the acute phase and in “steady state” in humans. In contrast to the T cells in the circulation, T cells derived from lymph nodes hardly contain any KLRG1-expressing cells. The four populations defined by IL-7Rα and KLRG1 differ markedly in transcription factor, granzyme and chemokine receptor expression. When studying renal transplant recipients experiencing a primary hCMV and EBV infection, we also found that after viral control, during latency, Ki-67-negative SLEC can be found in the peripheral blood in considerable numbers. Thus, combined analyses of IL-7Rα and KLRG1 expression on human herpes virus-specific CD8 + T cells can be used to separate functionally distinct subsets in humans. As a noncycling IL-7Rα lo KLRG1 hi population is abundant in healthy humans, we conclude that this combination of markers not only defines short-lived effector cells during the acute response but also stable effector cells that are formed and remain present during latent herpes infections.
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KLRG1 impairs regulatory t cell competitive fitness in the gut
Immunology, 2017Co-Authors: Holger Meinicke, Hanspeter Pircher, Anna Bremser, Maria Brack, Klaudia Schrenk, Ana IzcueAbstract:: Immune homeostasis requires the tight, tissue-specific control of the different CD4+ Foxp3+ regulatory T (Treg) cell populations. The cadherin-binding inhibitory receptor killer cell lectin-like receptor G1 (KLRG1) is expressed by a subpopulation of Treg cells with GATA3+ effector phenotype. Although such Treg cells are important for the immune balance, especially in the gut, the role of KLRG1 in Treg cells has not been assessed. Using KLRG1 knockout mice, we found that KLRG1 deficiency does not affect Treg cell frequencies in spleen, mesenteric lymph nodes or intestine, or frequencies of GATA3+ Treg cells in the gut. KLRG1-deficient Treg cells were also protective in a T-cell transfer model of colitis. Hence, KLRG1 is not essential for the development or activity of the general Treg cell population. We then checked the effects of KLRG1 on Treg cell activation. In line with KLRG1's reported inhibitory activity, in vitro KLRG1 cross-linking dampened the Treg cell T-cell receptor response. Consistently, lack of KLRG1 on Treg cells conferred on them a competitive advantage in the gut, but not in lymphoid organs. Hence, although absence of KLRG1 is not enough to increase intestinal Treg cells in KLRG1 knockout mice, KLRG1 ligation reduces T-cell receptor signals and the competitive fitness of individual Treg cells in the intestine.
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tgf β downregulates KLRG1 expression in mouse and human cd8 t cells
European Journal of Immunology, 2015Co-Authors: Sabrina Schwartzkopff, Sandra Woyciechowski, Ulrike Aichele, Tobias Flecken, Nu Zhang, Robert Thimme, Hanspeter PircherAbstract:: The inhibitory receptor killer cell lectin-like receptor G1 (KLRG1) and the integrin αE (CD103) are expressed by CD8(+) T cells and both are specific for E-cadherin. However, KLRG1 ligation by E-cadherin inhibits effector T-cell function, whereas binding of CD103 to E-cadherin enhances cell-cell interaction and promotes target cell lysis. Here, we demonstrate that KLRG1 and CD103 expression in CD8(+) T cells from untreated and virus-infected mice are mutually exclusive. Inverse correlation of KLRG1 and CD103 expression was also found in human CD8(+) T cells-infiltrating hepatocellular carcinomas. As TGF-β is known to induce CD103 expression in CD8(+) T cells, we examined whether this cytokine also regulates KLRG1 expression. Indeed, our data further reveal that TGF-β signaling in mouse as well as in human CD8(+) T cells downregulates KLRG1 expression. This finding provides a rationale for the reciprocal expression of KLRG1 and CD103 in different CD8(+) T-cell subsets. In addition, it points to the limitation of KLRG1 as a marker for terminally differentiated CD8(+) T cells if lymphocytes from tissues expressing high levels of TGF-β are analyzed.
Emilio Flaño - One of the best experts on this subject based on the ideXlab platform.
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Killer Cell Lectin-Like Receptor G1 Deficiency Significantly Enhances Survival after Mycobacterium tuberculosis Infection
Infection and Immunity, 2013Co-Authors: Joshua Cyktor, Hanspeter Pircher, Bridget Carruthers, Paul C. Stromberg, Emilio Flaño, Joanne TurnerAbstract:The expression of T cell differentiation markers is known to increase during Mycobacterium tuberculosis infection, and yet the biological role of such markers remains unclear. We examined the requirement of the T cell differentiation marker killer cell lectin-like receptor G1 (KLRG1) during M. tuberculosis infection using mice deficient in KLRG1. KLRG1−/− mice had a significant survival extension after M. tuberculosis infection compared to wild-type controls, and maintained a significantly lower level of pulmonary M. tuberculosis throughout chronic infection. Improved control of M. tuberculosis infection was associated with an increased number of activated pulmonary CD4+ T cells capable of secreting gamma interferon (IFN-γ). Our report is the first to show an in vivo impact of KLRG1 on disease control.
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contribution of pulmonary KLRG1 high and KLRG1 low cd8 t cells to effector and memory responses during influenza virus infection
Journal of Immunology, 2012Co-Authors: Fang Ye, Emilio Flaño, Joanne TurnerAbstract:In response to pathogen insult, CD8 T cells undergo expansion and a dynamic differentiation process into functionally different subpopulations. In this study, we show that during the effector response to influenza virus infection lung CD8 T cell subsets expressing killer cell lectin-like receptor G1 (KLRG1) high or KLRG1 low had similar effector functions and immediate recall efficacy. The KLRG1 expression profile of lung CD8 T cells was not permanent after adoptive transfer and recall. Airway CD8 T cells exhibited a unique phenotype expressing low levels of KLRG1 together with high levels of markers of cellular activation. We investigated the functional characteristics of these cells by analyzing their capacity to survive and to respond to a secondary challenge outside of the airway environment. KLRG1 high CD8 T cells isolated from the lung during the peak of the effector T cell response could survive for more than a month in the absence of cognate viral Ags after systemic adoptive transfer, and these “rested” CD8 T cells proliferated and participated in a recall response to influenza virus infection. These data highlight the unique phenotype and plasticity of effector CD8 T cell responses in the lung.
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Contribution of Pulmonary KLRG1high and KLRG1low CD8 T Cells to Effector and Memory Responses during Influenza Virus Infection
Journal of Immunology, 2012Co-Authors: Fang Ye, Joanne Turner, Emilio FlañoAbstract:In response to pathogen insult, CD8 T cells undergo expansion and a dynamic differentiation process into functionally different subpopulations. In this study, we show that during the effector response to influenza virus infection lung CD8 T cell subsets expressing killer cell lectin-like receptor G1 (KLRG1) high or KLRG1 low had similar effector functions and immediate recall efficacy. The KLRG1 expression profile of lung CD8 T cells was not permanent after adoptive transfer and recall. Airway CD8 T cells exhibited a unique phenotype expressing low levels of KLRG1 together with high levels of markers of cellular activation. We investigated the functional characteristics of these cells by analyzing their capacity to survive and to respond to a secondary challenge outside of the airway environment. KLRG1 high CD8 T cells isolated from the lung during the peak of the effector T cell response could survive for more than a month in the absence of cognate viral Ags after systemic adoptive transfer, and these “rested” CD8 T cells proliferated and participated in a recall response to influenza virus infection. These data highlight the unique phenotype and plasticity of effector CD8 T cell responses in the lung.
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KLRG1 nkg2a cd8 t cells mediate protection and participate in memory responses during γ herpesvirus infection
Journal of Immunology, 2011Co-Authors: Stephanie S Cush, Emilio FlañoAbstract:Functional CD8 T cell effector and memory responses are generated and maintained during murine γ-herpesvirus 68 (γHV68) persistent infection despite continuous presentation of viral lytic Ags. However, the identity of the CD8 T cell subpopulations that mediate effective recall responses and that can participate in the generation of protective memory to a γ-herpesvirus infection remains unknown. During γHV68 persistence, ∼75% of γHV68-specific CD8 T cells coexpress the NK receptors killer cell lectin-like receptor G1 (KLRG1) and NKG2A. In this study, we take advantage of this unique phenotype to analyze the capacity of CD8 T cells expressing or not expressing KLRG1 and NKG2A to mediate effector and memory responses. Our results show that γHV68-specific KLRG1+NKG2A+ CD8 T cells have an effector memory phenotype as well as characteristics of polyfunctional effector cells such us IFN-γ and TNF-α production, killing capacity, and are more efficient at protecting against a γHV68 challenge than their NKG2A−KLRG1− counterparts. Nevertheless, γHV68-specific NKG2A+KLRG1+ CD8 T cells express IL-7 and IL-15 receptors, can survive long-term without cognate Ag, and subsequently mount a protective response during antigenic recall. These results highlight the plasticity of the immune system to generate protective effector and proliferative memory responses during virus persistence from a pool of KLRG1+NKG2A+ effector memory CD8 T cells.
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KLRG1+NKG2A+ CD8 T Cells Mediate Protection and Participate in Memory Responses during γ-Herpesvirus Infection
Journal of Immunology, 2011Co-Authors: Stephanie S Cush, Emilio FlañoAbstract:Functional CD8 T cell effector and memory responses are generated and maintained during murine γ-herpesvirus 68 (γHV68) persistent infection despite continuous presentation of viral lytic Ags. However, the identity of the CD8 T cell subpopulations that mediate effective recall responses and that can participate in the generation of protective memory to a γ-herpesvirus infection remains unknown. During γHV68 persistence, ∼75% of γHV68-specific CD8 T cells coexpress the NK receptors killer cell lectin-like receptor G1 (KLRG1) and NKG2A. In this study, we take advantage of this unique phenotype to analyze the capacity of CD8 T cells expressing or not expressing KLRG1 and NKG2A to mediate effector and memory responses. Our results show that γHV68-specific KLRG1+NKG2A+ CD8 T cells have an effector memory phenotype as well as characteristics of polyfunctional effector cells such us IFN-γ and TNF-α production, killing capacity, and are more efficient at protecting against a γHV68 challenge than their NKG2A−KLRG1− counterparts. Nevertheless, γHV68-specific NKG2A+KLRG1+ CD8 T cells express IL-7 and IL-15 receptors, can survive long-term without cognate Ag, and subsequently mount a protective response during antigenic recall. These results highlight the plasticity of the immune system to generate protective effector and proliferative memory responses during virus persistence from a pool of KLRG1+NKG2A+ effector memory CD8 T cells.
David Voehringer - One of the best experts on this subject based on the ideXlab platform.
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the nk receptor KLRG1 is dispensable for virus induced nk and cd8 t cell differentiation and function in vivo
European Journal of Immunology, 2010Co-Authors: Carsten Grundemann, Oliver Schweier, David Voehringer, Marie Koschella, Sabrina Schwartzkopff, Christoph Peters, Hanspeter PircherAbstract:The killer cell lectin-like receptor G1 (KLRG1) is expressed by NK and T-cell subsets and recognizes members of the classical cadherin family. KLRG1 is widely used as a lymphocyte differentiation marker in both humans and mice but the physiological role of KLRG1 in vivo is still unclear. Here, we generated KLRG1-deficient mice by homologous recombination and used several infection models for their characterization. The results revealed that KLRG1 deficiency did not affect development and function of NK cells examined under various conditions. KLRG1 was also dispensable for normal CD8+ T-cell differentiation and function after viral infections. Thus, KLRG1 is a marker for distinct NK and T-cell differentiation stages but it does not play a deterministic role in the generation and functional characteristics of these lymphocyte subsets. In addition, we demonstrate that E-cadherin expressed by K562 target cells inhibited NK-cell reactivity in transgenic mice over-expressing KLRG1 but not in KLRG1-deficient or WT mice. Hence, the inhibitory potential of KLRG1 in mice is rather weak and strong activation signals during viral infections may override the inhibitory signal in vivo.
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frequent expression of the natural killer cell receptor KLRG1 in human cord blood t cells correlation with replicative history
European Journal of Immunology, 2004Co-Authors: Isabel Marcolino, David Voehringer, Marie Koschella, Grzegorz K Przybylski, Christian A Schmidt, Michael Schlesier, Hanspeter PircherAbstract:The killer cell lectin-like receptor G1 (KLRG1) belongs to the family of inhibitory C-type lectins that are encoded in the NK gene complex. Similar to other inhibitory NK cell receptors, KLRG1 expression in adult peripheral blood lymphocytes is restricted to NK cells and to antigen-experienced T cells. Umbilical cord blood T cells are thought to represent an homogenous pool of naive T cells. Surprisingly, we identified substantial subsets of CD4 (∼ 30%) and CD8 (∼ 20%) αβ T cells in cord blood that expressed KLRG1. In contrast to T cells in adult, KLRG1+ T cells in cord blood exhibited predominantly a naive CCR7+CD45RA+ and CD11alow phenotype. After birth, KLRG1 expression in T cells from peripheral blood decreased rapidly to reappear in effector/memory T cells in adults. KLRG1+ T cells in cord blood expressed a diverse T cell receptor β (TCRβ) repertoire and the cells proliferated normally, in contrast to KLRG1+ T cells from adults. Finally, examination of T cell receptor excision circles (TREC) indicated that KLRG1 expression discriminated between cord blood T cells that differed in their post-thymic expansion rate. Thus, analysis of KLRG1 expression in cord blood revealed an unexpected heterogeneity of human T cells in newborns.
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age associated accumulation of cmv specific cd8 t cells expressing the inhibitory killer cell lectin like receptor g1 KLRG1
Experimental Gerontology, 2003Co-Authors: Qin Ouyang, Hanspeter Pircher, David Voehringer, Wolfgang Wagner, Anders Wikby, Tatjana Klatt, Steffen Walter, C A Muller, Graham PawelecAbstract:Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1)
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lack of proliferative capacity of human effector and memory t cells expressing killer cell lectinlike receptor g1 KLRG1
Blood, 2002Co-Authors: David Voehringer, Marie Koschella, Hanspeter PircherAbstract:Adaptive immunity necessitates the proliferation of lymphocytes. In the mouse, we have previously shown that antigen-experienced T cells that have lost their proliferative potential express the killer cell lectinlike receptor G1 (KLRG1). By using a newly generated monoclonal antibody specific for human KLRG1, we now demonstrate that expression of KLRG1 also identifies T cells in humans that are capable of secreting cytokines but that fail to proliferate after stimulation. Furthermore, our data show that proliferative incapacity of CD8 T cells correlates better with KLRG1 expression than with absence of the CD28 marker. In peripheral blood lymphocytes (PBLs) from healthy adult donors, KLRG1 was expressed on 44% ± 14% of CD8 and 18% ± 10% of CD4 T cells. KLRG1 expression was restricted to antigen-experienced T cells. Here, KLRG1+ cells were preferentially found in the CCR7− effector T-cell pool. Besides T cells, a significant portion (approximately 50%) of human natural killer (NK) cells expressed KLRG1. Interestingly, these KLRG1+ NK cells were found exclusively in the CD56dim NK-cell subset. Thus, the expression of KLRG1 identifies a subset of NK cells and antigen-experienced T cells in humans that lack proliferative capacity.
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Viral Infections Induce Abundant Numbers of Senescent CD8 T Cells
Journal of Immunology, 2001Co-Authors: David Voehringer, Thomas Hanke, David H Raulet, Claudine Blaser, Pierre Brawand, Hanspeter PircherAbstract:Viral infections are often accompanied by extensive proliferation of reactive CD8 T cells. After a defined number of divisions, normal somatic cells enter a nonreplicative stage termed senescence. In the present study we have identified the inhibitory killer cell lectin-like receptor G1 (KLRG1) as a unique marker for replicative senescence of murine CD8 T cells. KLRG1 expression was induced in a substantial portion (30–60%) of CD8 T cells in C57BL/6 mice infected with lymphocytic choriomeningitis virus (LCMV), vesicular stomatitis virus, or vaccinia virus. Similarly, KLRG1 was found on a large fraction of LCMV gp33 peptide-specific TCR-transgenic (tg) effector and memory cells activated in vivo using an adoptive transfer model. Transfer experiments with CFSE-labeled TCR-tg cells into LCMV-infected hosts further indicated that induction of KLRG1 expression required an extensive number of cell divisions. Most importantly, KLRG1 + TCR-tg effector/memory cells could efficiently lyse target cells and secrete cytokines, but were severely impaired in their ability to proliferate after Ag stimulation. Thus, this study demonstrates that senescent CD8 T cells are induced in abundant numbers during viral infections in vivo.
Robert Thimme - One of the best experts on this subject based on the ideXlab platform.
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tgf β downregulates KLRG1 expression in mouse and human cd8 t cells
European Journal of Immunology, 2015Co-Authors: Sabrina Schwartzkopff, Sandra Woyciechowski, Ulrike Aichele, Tobias Flecken, Nu Zhang, Robert Thimme, Hanspeter PircherAbstract:: The inhibitory receptor killer cell lectin-like receptor G1 (KLRG1) and the integrin αE (CD103) are expressed by CD8(+) T cells and both are specific for E-cadherin. However, KLRG1 ligation by E-cadherin inhibits effector T-cell function, whereas binding of CD103 to E-cadherin enhances cell-cell interaction and promotes target cell lysis. Here, we demonstrate that KLRG1 and CD103 expression in CD8(+) T cells from untreated and virus-infected mice are mutually exclusive. Inverse correlation of KLRG1 and CD103 expression was also found in human CD8(+) T cells-infiltrating hepatocellular carcinomas. As TGF-β is known to induce CD103 expression in CD8(+) T cells, we examined whether this cytokine also regulates KLRG1 expression. Indeed, our data further reveal that TGF-β signaling in mouse as well as in human CD8(+) T cells downregulates KLRG1 expression. This finding provides a rationale for the reciprocal expression of KLRG1 and CD103 in different CD8(+) T-cell subsets. In addition, it points to the limitation of KLRG1 as a marker for terminally differentiated CD8(+) T cells if lymphocytes from tissues expressing high levels of TGF-β are analyzed.
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analysis of cd127 and KLRG1 expression on hepatitis c virus specific cd8 t cells reveals the existence of different memory t cell subsets in the peripheral blood and liver
Journal of Virology, 2007Co-Authors: Bertram Bengsch, Hanspeter Pircher, E Panther, Hubert E Blum, Hans Christian Spangenberg, Nadine Kersting, Christoph Neumannhaefelin, Fritz Von Weizsacker, Robert ThimmeAbstract:The differentiation and functional status of virus-specific CD8 + T cells is significantly influenced by specific and ongoing antigen recognition. Importantly, the expression profiles of the interleukin-7 receptor alpha chain (CD127) and the killer cell lectin-like receptor G1 (KLRG1) have been shown to be differentially influenced by repetitive T-cell receptor interactions. Indeed, antigen-specific CD8 + T cells targeting persistent viruses (e.g., human immunodeficiency virus and Epstein-Barr virus) have been shown to have low CD127 and high KLRG1 expressions, while CD8 + T cells targeting resolved viral antigens (e.g., FLU) typically display high CD127 and low KLRG1 expressions. Here, we analyzed the surface phenotype and function of hepatitis C virus (HCV)-specific CD8 + T cells. Surprisingly, despite viral persistence, we found that a large fraction of peripheral HCV-specific CD8 + T cells were CD127 + and KLRG1 − and had good proliferative capacities, thus resembling memory cells that usually develop following acute resolving infection. Intrahepatic virus-specific CD8 + T cells displayed significantly reduced levels of CD127 expression but similar levels of KLRG1 expression compared to the peripheral blood. These results extend previous studies that demonstrated central memory (CCR7 + ) and early-differentiated phenotypes of HCV-specific CD8 + T cells and suggest that insufficient stimulation of virus-specific CD8 + T cells by viral antigen may be responsible for this alteration in HCV-specific CD8 + T-cell differentiation during chronic HCV infection.
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increased expression of the nk cell receptor KLRG1 by virus specific cd8 t cells during persistent antigen stimulation
Journal of Virology, 2005Co-Authors: Robert Thimme, Marie Koschella, Victor Appay, E Panther, Evelyn Roth, Andrew D Hislop, Alan B Rickinson, Sarah Rowlandjones, Hubert E Blum, Hanspeter PircherAbstract:The killer cell lectin-like receptor G1 (KLRG1) is a natural killer cell receptor expressed by T cells that exhibit impaired proliferative capacity. Here, we determined the KLRG1 expression by virus-specific T cells. We found that repetitive and persistent antigen stimulation leads to an increase in KLRG1 expression of virus-specific CD8 + T cells in mice and that virus-specific CD8 + T cells are mostly KLRG1 + in chronic human viral infections (human immunodeficiency virus, cytomegalovirus, and Epstein-Barr virus) but not in resolved infection (influenza virus). Thus, by using KLRG1 as a T-cell marker, our results suggest that the differentiation status and function of virus-specific CD8 + T cells are directly influenced by persistent antigen stimulation.
Thomas Hanke - One of the best experts on this subject based on the ideXlab platform.
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characterization of mouse cd4 t cell subsets defined by expression of KLRG1
European Journal of Immunology, 2007Co-Authors: Niklas Beyersdorf, Xin Ding, Julia K Tietze, Thomas HankeAbstract:The mouse killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor known to be expressed on a subset of NK cells and antigen-experienced CD8 T cells. Here, we have characterized expression of KLRG1 on CD4+ T cells from normal mice. While a polyclonal TCR repertoire suggests thymic origin of KLRG1+ CD4+ cells, KLRG1 expression was found to be restricted to peripheral CD4+ T cells. Based on phenotypic analyses, a minority of KLRG1+ CD4+ cells are effector/memory cells with a proliferative history. The majority of KLRG1+ CD4+ cells are, however, bona fide Treg cells that depend on IL-2 and/or CD28 and express both FoxP3 and high levels of intracellular CD152. KLRG1-expressing Treg are contained within the CD38+ subset but are only partially overlapping with the CD25+ CD4+ Treg subset. In functional assays, KLRG1+ CD4+ cells were anergic to TCR stimulation with respect to proliferation, and sorted KLRG1+ CD25+ CD4+ cells were equal or superior to KLRG1+ CD25– CD4+ cells, which were more potent than KLRG1– CD25+ CD4+ cells in suppressing responder cell proliferation. Together, our results demonstrate that KLRG1 expression defines novel and distinctive subsets of senescent effector/memory and potent regulatory CD4+ T cells.
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Cutting Edge: Identification of E-Cadherin as a Ligand for the Murine Killer Cell Lectin-Like Receptor G1
Journal of Immunology, 2006Co-Authors: Carsten Grundemann, Oliver Schweier, Thomas Hanke, Klaus Karp, Karl-friedrich Becker, Monika Bauer, Nanette Von Oppen, Ute Lässing, Philippe Saudan, Martin F. BachmannAbstract:The killer cell lectin-like receptor G1 (KLRG1) is expressed by NK cells and by T cells. In both humans and mice, KLRG1 identifies Ag-experienced T cells that are impaired in their proliferative capacity but are capable of performing effector functions. In this study, we identified E-cadherin as a ligand for murine KLRG1 by using fluorescently labeled, soluble tetrameric complexes of the extracellular domain of the murine KLRG1 molecule as staining reagents in expression cloning. Ectopic expression of E-cadherin in B16.BL6 target cells did not affect cell-mediated lysis by lymphokine-activated NK cells and by CD8 T cells but inhibited Ag-induced proliferation and induction of cytolytic activity of CD8 T cells. E-cadherin is expressed by normal epithelial cells, Langerhans cells, and keratinocytes and is usually down-regulated on metastatic cancer cells. KLRG1 ligation by E-cadherin in healthy tissue may thus exert an inhibitory effect on primed T cells.
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Expression of inhibitory "killer cell lectin-like receptor G1" identifies unique subpopulations of effector and memory CD8 T cells
European Journal of Immunology, 2001Co-Authors: Niklas Beyersdorf, Xin Ding, Klaus Karp, Thomas HankeAbstract:T cell and natural killer (NK) cell functions are regulated by triggering of activating and inhibitory cell surface receptors. Here, we have studied the expression profile and predicted inhibitory function of mouse "killer cell lectin-like receptor G1" (KLRG1) on CD8 T cells. KLRG1 was present on 1 – 3 % of adult splenic CD8 cells that expressed CD8α β heterodimers as well as a polyclonal TCR Vβ repertoire indicative of conventional CD8 cells. The majority of KLRG1+ CD8 cells belonged to the memory pool as determined by extensive phenotypic marker analysis. Spontaneous IFN-γ production by approximately 20 % of KLRG1+ CD8 cells identified them as pro-inflammatory effector cells. In contrast to NK cells, Ly49 and KLRG1 expression on CD8cells was found to be mutually exclusive. Therefore, distinct programs regulate KLRG1 expression in CD8 and NK cells. Finally, we provide evidence that KLRG1 triggering interferes with TCRα β-mediated Ca++ mobilization and cytotoxicity, raising the possibility that KLRG1 functionally participates in down-regulation of CD8 T cell responses.
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Viral Infections Induce Abundant Numbers of Senescent CD8 T Cells
Journal of Immunology, 2001Co-Authors: David Voehringer, Thomas Hanke, David H Raulet, Claudine Blaser, Pierre Brawand, Hanspeter PircherAbstract:Viral infections are often accompanied by extensive proliferation of reactive CD8 T cells. After a defined number of divisions, normal somatic cells enter a nonreplicative stage termed senescence. In the present study we have identified the inhibitory killer cell lectin-like receptor G1 (KLRG1) as a unique marker for replicative senescence of murine CD8 T cells. KLRG1 expression was induced in a substantial portion (30–60%) of CD8 T cells in C57BL/6 mice infected with lymphocytic choriomeningitis virus (LCMV), vesicular stomatitis virus, or vaccinia virus. Similarly, KLRG1 was found on a large fraction of LCMV gp33 peptide-specific TCR-transgenic (tg) effector and memory cells activated in vivo using an adoptive transfer model. Transfer experiments with CFSE-labeled TCR-tg cells into LCMV-infected hosts further indicated that induction of KLRG1 expression required an extensive number of cell divisions. Most importantly, KLRG1 + TCR-tg effector/memory cells could efficiently lyse target cells and secrete cytokines, but were severely impaired in their ability to proliferate after Ag stimulation. Thus, this study demonstrates that senescent CD8 T cells are induced in abundant numbers during viral infections in vivo.
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nk cell expression of the killer cell lectin like receptor g1 KLRG1 the mouse homolog of mafa is modulated by mhc class i molecules
European Journal of Immunology, 2000Co-Authors: Laura Corral, Thomas Hanke, Russell E Vance, Dragana Cado, David H RauletAbstract:Department of Molecular and Cell Biology and Cancer Research Laboratory, University ofCalifornia, Berkeley, USAUsing a new mAb, 2F1, we characterize a mouse natural killer (NK) cell antigen termed ‘killercell lectin-like receptor G1’ (KLRG1; formerly mouse MAFA or 2F1-Ag). KLRG1 is expressedon 30–60% of murine NK cells, and a small fraction of T cells, and is composed of a homo-dimer of glycosylated 30–38-kDa subunits. Strikingly, cell surface expression of KLRG1 byNK cells was substantially down-regulated in mice deficient for expression of class I mole-cules, in contrast to the Ly49 lectin-like NK receptors, which are up-regulated in class I-deficient mice. We could not demonstrate binding of KLRG1 to class I molecules in a cell-cell adhesion assay. Transgenic expression of KLRG1 under heterologous transcription ele-ments was unaffected by class I deficiency, indicating that class I molecules do not affectthe KLRG1 protein directly, and suggesting that regulation is at the level of expression of theendogenous KLRG1 gene. Evidence is presented that class I molecules regulate KLRG1 viainteractions with class I-specific inhibitory Ly49 molecules and SHP-1 signaling. Thus,although KLRG1 and Ly49 molecules are both lectin-like inhibitory receptors that are regu-lated by class I expression, the effects of class I on the cell surface expression of the mole-cules are opposing, and the underlying regulatory mechanisms are distinct.