scholarly journals Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates

2008 ◽  
Vol 205 (3) ◽  
pp. 625-640 ◽  
Author(s):  
Surojit Sarkar ◽  
Vandana Kalia ◽  
W. Nicholas Haining ◽  
Bogumila T. Konieczny ◽  
Shruti Subramaniam ◽  
...  
Keyword(s):  
T Cells ◽  
Expression Profiles ◽  
Acute Infection ◽  
Killer Cell ◽  
Gene Expression Profiles ◽  
Antigenic Stimulation ◽  
T Cell Subsets ◽  
Genomic Profiling ◽  
Memory Cells ◽  
Effector Cells

An important question in memory development is understanding the differences between effector CD8 T cells that die versus effector cells that survive and give rise to memory cells. In this study, we provide a comprehensive phenotypic, functional, and genomic profiling of terminal effectors and memory precursors. Using killer cell lectin-like receptor G1 as a marker to distinguish these effector subsets, we found that despite their diverse cell fates, both subsets possessed remarkably similar gene expression profiles and functioned as equally potent killer cells. However, only the memory precursors were capable of making interleukin (IL) 2, thus defining a novel effector cell that was cytotoxic, expressed granzyme B, and produced inflammatory cytokines in addition to IL-2. This effector population then differentiated into long-lived protective memory T cells capable of self-renewal and rapid recall responses. Experiments to understand the signals that regulate the generation of terminal effectors versus memory precursors showed that cells that continued to receive antigenic stimulation during the later stages of infection were more likely to become terminal effectors. Importantly, curtailing antigenic stimulation toward the tail end of the acute infection enhanced the generation of memory cells. These studies support the decreasing potential model of memory differentiation and show that the duration of antigenic stimulation is a critical regulator of memory formation.

scholarly journals KIR+ CD8+ T Lymphocytes in Cancer Immunosurveillance and Patient Survival: Gene Expression Profiling

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2991
Author(s):  
Lourdes Gimeno ◽  
Emilio M. Serrano-López ◽  
José A. Campillo ◽  
María A. Cánovas-Zapata ◽  
Omar S. Acuña ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Cd8 T Cells ◽  
Expression Profiles ◽  
Killer Cell ◽  
Gene Expression Profiles ◽  
Gene Expression Signature ◽  
Oncologic Patients ◽  
Survival Gene ◽  
Cancer Immunosurveillance

Killer-cell immunoglobulin-like receptors (KIR) are expressed by natural killer (NK) and effector T cells. Although KIR+ T cells accumulate in oncologic patients, their role in cancer immune response remains elusive. This study explored the role of KIR+CD8+ T cells in cancer immunosurveillance by analyzing their frequency at diagnosis in the blood of 249 patients (80 melanomas, 80 bladder cancers, and 89 ovarian cancers), their relationship with overall survival (OS) of patients, and their gene expression profiles. KIR2DL1+ CD8+ T cells expanded in the presence of HLA-C2-ligands in patients who survived, but it did not in patients who died. In contrast, presence of HLA-C1-ligands was associated with dose-dependent expansions of KIR2DL2/S2+ CD8+ T cells and with shorter OS. KIR interactions with their specific ligands profoundly impacted CD8+ T cell expression profiles, involving multiple signaling pathways, effector functions, the secretome, and consequently, the cellular microenvironment, which could impact their cancer immunosurveillance capacities. KIR2DL1/S1+ CD8+ T cells showed a gene expression signature related to efficient tumor immunosurveillance, whereas KIR2DL2/L3/S2+CD8+ T cells showed transcriptomic profiles related to suppressive anti-tumor responses. These results could be the basis for the discovery of new therapeutic targets so that the outcome of patients with cancer can be improved.

scholarly journals Regulatory T cells differentially modulate the maturation and apoptosis of human CD8+ T-cell subsets

Blood ◽  
2009 ◽  
Vol 113 (19) ◽  
pp. 4556-4565 ◽  
Author(s):  
Maria Nikolova ◽  
Jean-Daniel Lelievre ◽  
Matthieu Carriere ◽  
Armand Bensussan ◽  
Yves Lévy
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Effector Cell ◽  
Cd8 T Cell ◽  
Treg Cells ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Memory Cells ◽  
Effector Cells

Abstract The balanced manifestation of effector functions and the generation of long-living memory cells is a hallmark of efficient CD8+ T-cell response. Accumulating data pinpoint CD4+ CD25high regulatory T (Treg) cells as a key factor for the inefficiency of CD8+ T-cell responses in viral persistence. Little is known about the effects of Treg cells on the homeostasis of healthy donor CD8+ T cells. The present study demonstrates that Treg cells exert differential effects on CD8+ T-cell subsets. Treg cells inhibited mostly the polyclonal proliferation of CD27− effector cells compared with CD27+ memory CD8+ T cells. Moreover, they inhibited the polyclonal and antigen-driven differentiation of memory cells into functional effectors as defined by IFN-γ secretion and induction of CD160 expression. Finally, Treg cells reduced the apoptosis of memory but not of effector and terminal effector cell populations. These effects were at least in part mediated by a decreased expression of PD-L1, but not of programmed death 1 (PD-1), on CD8+ T cells after activation. Thus, in the setting of a healthy immune system, Treg cells fine-tune the memory/effector cell balance and promote the accumulation of long-living memory cells in case of strong stimulation.

scholarly journals Migratory Properties of Naive, Effector, and Memory Cd8+ T Cells

2001 ◽  
Vol 194 (7) ◽  
pp. 953-966 ◽  
Author(s):  
Wolfgang Weninger ◽  
Maura A. Crowley ◽  
N. Manjunath ◽  
Ulrich H. von Andrian
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Lymphoid Organs ◽  
Central Memory ◽  
T Cell Subsets ◽  
Memory Cells ◽  
Effector Cells ◽  
Central Memory Cells ◽  
Cells Cultured

It has been proposed that two different antigen-experienced T cell subsets may be distinguishable by their preferential ability to home to lymphoid organs (central memory cells) or nonlymphoid tissues (effector memory/effector cells). We have shown recently that murine antigen-primed CD8+ T cells cultured in interleukin (IL)-15 (CD8IL-15) resemble central memory cells in phenotype and function. In contrast, primed CD8+ T cells cultured in IL-2 (CD8IL-2) become cytotoxic effector cells. Here, the migratory behavior of these two subsets was investigated. Naive, CD8IL-15 cells and, to a lesser degree, CD8IL-2 cells localized to T cell areas in the spleen, but only naive and CD8IL-15 cells homed to lymph nodes (LNs) and Peyer's patches. Intravital microscopy of peripheral LNs revealed that CD8IL-15 cells, but not CD8IL-2 cells, rolled and arrested in high endothelial venules (HEVs). Migration of CD8IL-15 cells to LNs depended on L-selectin and required chemokines that bind CC chemokine receptor (CCR)7. Both antigen-experienced populations, but not naive T cells, responded to inflammatory chemokines and accumulated at sites of inflammation. However, CD8IL-2 cells were 12 times more efficient in migrating to inflamed peritoneum than CD8IL-15 cells. Furthermore, CD8IL-15 cells proliferated rapidly upon reencounter with antigen at sites of inflammation. Thus, central memory-like CD8IL-15 cells home avidly to lymphoid organs and moderately to sites of inflammation, where they mediate rapid recall responses, whereas CD8IL-2 effector T cells accumulate in inflamed tissues, but are excluded from most lymphoid organs.

All Memory Lymphocytes Share a Common Differentiation Program.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 865-865
Author(s):  
W. Nicholas Haining ◽  
Benjamin Ebert ◽  
Aravind Subramanian ◽  
E. John Wherry ◽  
John Evans ◽  
...  
Keyword(s):  
T Cells ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Human Memory ◽  
Memory Cells ◽  
Cell Memory ◽  
Cd8 Cells ◽  
Transcriptional Signature ◽  
Memory Differentiation ◽  
Lcmv Infection

Abstract Although memory lymphocytes in CD4, CD8 and B cell lineages are characterized by a strikingly diverse array of functions and phenotypes, they share common properties of longevity, lowered response threshold and the ability to self-renew. The development of these memory functions is essential for immunity to pathogens and tumors, but it is not known how diverse lineages acquire these same properties. We therefore studied the transcriptional profile of memory differentiation to determine whether the development of memory in disparate lineages involves a common differentiation program. To identify a core signature of memory differentiation, we used cross-species genomic analysis to identify genes differentially expressed by both human and murine memory CD8 T cells compared to their naive precursors. We identified 220 genes significantly increased in human memory-phenotype cells, and found this signature to be highly conserved in two different TCR transgenic murine models of memory differentiation (P<0.001). Our analysis thus revealed an evolutionarily conserved transcriptional signature of CD memory differentiation. Several of the genes in this signature are known to be required for CD8 memory development, while others are novel markers of memory differentiation. We validated the signature at the protein and functional level, and demonstrated that it is highly enriched in the gene expression profiles of human CD8 T cells specific for CMV, influenza and EBV, suggesting that diverse viral pathogens can induce a similar differentiation program. We next tested whether this conserved signature is necessary for memory cells to be fully functional. To address this question, we studied memory differentiation in TCR transgenic T cells responding acute or chronic LCMV infection. Adult mice resolve an acute LCMV infection and then exhibit long-term CD8 T cell memory. In contrast, chronic LCMV infection results in exhausted CD8 cells that fail to demonstrate the properties of memory cells. Hierarchical clustering of the memory signature genes showed marked differences between functional memory cells and virally-exhausted T cells. Thus the signature of memory differentiation is disrupted in CD8 cells that fail to manifest the properties of memory. Finally, we tested the conserved CD8 memory signature in gene expression profiles of human memory CD4 and memory B cells compared to their naïve precursors. We found that the CD8 memory signature was highly enriched not only in CD4 memory (P<0.001) but also in B cell memory (P<0.001). Thus a single transcriptional signature is a general feature of memory differentiation in CD8, CD4 and B cells, and disruption of this signature is associated with defective T cell memory. Analysis of the regulation of this transcriptional program may help identify the mechanisms governing memory differentiation. Our data represent a novel approach to predicting the function of antigen-specific memory cells in vivo, and suggest that drugs which target this single differentiation program could profoundly influence the formation of immunologic memory.

scholarly journals 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

2006 ◽  
Vol 81 (2) ◽  
pp. 945-953 ◽  
Author(s):  
Bertram Bengsch ◽  
Hans Christian Spangenberg ◽  
Nadine Kersting ◽  
Christoph Neumann-Haefelin ◽  
Elisabeth Panther ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
Peripheral Blood ◽  
Expression Profiles ◽  
Large Fraction ◽  
Killer Cell ◽  
Cell Receptor ◽  
T Cell Subsets

ABSTRACT 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.

scholarly journals Immunomodulating nano-adaptors potentiate antibody-based cancer immunotherapy

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Cheng-Tao Jiang ◽  
Kai-Ge Chen ◽  
An Liu ◽  
Hua Huang ◽  
Ya-Nan Fan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cancer Immunotherapy ◽  
Tumor Cells ◽  
Noncovalent Interactions ◽  
Killer Cell ◽  
Antibody Immobilization ◽  
Effector Cells ◽  
Nanoparticle Surface

AbstractModulating effector immune cells via monoclonal antibodies (mAbs) and facilitating the co-engagement of T cells and tumor cells via chimeric antigen receptor- T cells or bispecific T cell-engaging antibodies are two typical cancer immunotherapy approaches. We speculated that immobilizing two types of mAbs against effector cells and tumor cells on a single nanoparticle could integrate the functions of these two approaches, as the engineered formulation (immunomodulating nano-adaptor, imNA) could potentially associate with both cells and bridge them together like an ‘adaptor’ while maintaining the immunomodulatory properties of the parental mAbs. However, existing mAbs-immobilization strategies mainly rely on a chemical reaction, a process that is rough and difficult to control. Here, we build up a versatile antibody immobilization platform by conjugating anti-IgG (Fc specific) antibody (αFc) onto the nanoparticle surface (αFc-NP), and confirm that αFc-NP could conveniently and efficiently immobilize two types of mAbs through Fc-specific noncovalent interactions to form imNAs. Finally, we validate the superiority of imNAs over the mixture of parental mAbs in T cell-, natural killer cell- and macrophage-mediated antitumor immune responses in multiple murine tumor models.

696 Brentuximab vedotin, a CD30-directed antibody-drug conjugate, selectively depletes activated Tregs in vitro and in vivo

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A738-A738
Author(s):  
Bryan Grogan ◽  
Reice James ◽  
Michelle Ulrich ◽  
Shyra Gardai ◽  
Ryan Heiser ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Efflux Pump ◽  
Apoptotic Cell ◽  
T Cell Subsets ◽  
Memory Cells ◽  
Antibody Drug Conjugate ◽  
Selective Depletion

BackgroundRegulatory T cells (Tregs) play an important role in maintaining immune homeostasis, preventing excessive inflammation in normal tissues. In cancer, Tregs hamper anti-tumor immunosurveillance and facilitate immune evasion. Selective targeting of intratumoral Tregs is a potentially promising treatment approach. Orthogonal evaluation of tumor-infiltrating lymphocytes (TILs) in solid tumors in mice and humans have identified CCR8, and several tumor necrosis family receptors (TNFRs), including TNFSFR8 (CD30), as receptors differentially upregulated on intratumoral Tregs compared to normal tissue Tregs and other intratumoral T cells, making these intriguing therapeutic targets.Brentuximab vedotin (BV) is approved for classical Hodgkin lymphoma (cHL) across multiple lines of therapy including frontline use in stage III/IV cHL in combination with doxorubicin, vinblastine, and dacarbazine. BV is also approved for certain CD30-expressing T-cell lymphomas. BV is comprised of a CD30-directed monoclonal antibody conjugated to the highly potent microtubule-disrupting agent monomethyl auristatin E (MMAE).The activity of BV in lymphomas is thought to primarily result from tumor directed intracellular MMAE release, leading to mitotic arrest and apoptotic cell death.The role CD30 plays in normal immune function is unclear, with both costimulatory and proapoptotic roles described. CD30 is transiently upregulated following activation of memory T cells and expression has been linked to highly activated/suppressive IRF4+ effector Tregs.MethodsHere we evaluated the activity of BV on CD30-expressing T cell subsets in vitro and in vivo.ResultsTreatment of enriched T cell subsets with clinically relevant concentrations of BV drove selective depletion of CD30-expressing Tregs > CD30-expressingCD4+ T memory cells, with minimal effects on CD30-expressing CD8+ T memory cells. In a humanized xeno-GVHD model, treatment with BV selectively depleted Tregs resulting in accelerated wasting and robust T cell expansion. The observed differential activity on Tregs is likely attributable to significant increases in CD30 expression and reduced efflux pump activity relative to other T cell subsets. Interestingly, blockade of CD25 signaling prevents CD30 expression on T cell subsets without impacting proliferation, suggesting a link between CD25, the high affinity IL-2 receptor, and CD30 expression.ConclusionsTogether, these data suggest that BV may have an immunomodulatory effect through selective depletion of highly suppressive CD30-expressing Tregs.AcknowledgementsThe authors would like to thank Michael Harrison, PharmD for their assistance in abstract preparation.Ethics ApprovalAnimals studies were approved by and conducted in accordance with Seattle Genetics Institutional Care and Use Committee protocol #SGE-024.

scholarly journals GeneExpression in HL60 Granulocytoids and Human PolymorphonuclearLeukocytes Exposed to Candidaalbicans†

2004 ◽  
Vol 72 (1) ◽  
pp. 414-429 ◽  
Author(s):  
Alaka Mullick ◽  
Miria Elias ◽  
Penelope Harakidas ◽  
Anne Marcil ◽  
Malcolm Whiteway ◽  
...  
Keyword(s):  
Gene Expression ◽  
Polymorphonuclear Leukocytes ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Dimorphic Fungus ◽  
Granulocytic Differentiation ◽  
Effector Cells ◽  
Study Gene Expression ◽  
Opportunistic Human Pathogen ◽  
Human Polymorphonuclear Leukocytes

ABSTRACT Candida albicans is an opportunistic human pathogen causing both superficial and disseminated diseases. It is a dimorphic fungus, switching between yeast and hyphal forms, depending on cues from its microenvironment. Hyphae play an important role in the pathogenesis of candidiasis. The host's response to Candida infection is multifaceted and includes the participation of granulocytes as key effector cells. The aim of this investigation was to study host gene expression during granulocyte-Candida interaction. Effector cells were generated by the granulocytic differentiation of HL60 cells. The resulting cell population was shown to be morphologically and functionally equivalent to granulocytes and is therefore referred to as HL60 granulocytoids for the purposes of this study. Gene expression profiles were determined 1 h after hosts were infected with C. albicans. Three Candida-granulocytoid ratios were chosen to reflect different degrees of HL60 granulocytoid inhibition of C. albicans. The data demonstrate that at the high pathogen-host ratio, C. albicans modulated the HL60 granulocytoid's response by downregulating the expression of known antimicrobial genes. In addition, looking at the expression of a large number of genes, not all of which have necessarily been implicated in candidastatic or candidacidal mechanisms, it has been possible to describe the physiological response of the HL60 granulocytoid to an infectious challenge with C. albicans. Finally, some of the observed changes in HL60 granulocytoid gene expression were investigated in freshly isolated human polymorphonuclear leukocytes infected with C. albicans. Similar changes were seen in these primary human cells, lending support to the validity of this model.

scholarly journals Functional analysis of T cells expressing Ia antigens. I. Demonstration of helper T-cell heterogeneity.

1979 ◽  
Vol 150 (6) ◽  
pp. 1293-1309 ◽  
Author(s):  
J E Swierkosz ◽  
P Marrack ◽  
J W Kappler
Keyword(s):  
T Cells ◽  
T Cell ◽  
Keyhole Limpet Hemocyanin ◽  
T Cell Subsets ◽  
Cytotoxic Lymphocytes ◽  
Lymphocyte Function ◽  
Con A ◽  
Helper T Cell ◽  
Effector Cells ◽  
Ia Antigens

We have examined the expression of I-region antigens on functional subpopulations of murine T cells. A.TH anti-A.TL (anti-Ik, Sk, Gk) alloantiserum was raised by immunization of recipients with concanavalin A (Con A) stimulated thymic and peripheral T-cell blasts. In contrast to similar antisera made by conventional methods, the anti-Ia blast serum was highly cytotoxic for purified T lymphocytes. Moreover, it reacted in a specific fashion with T cells having particular functions. Treatment of keyhole limpet hemocyanin (KLH)-primed B10.A (H-2 alpha) T cells with this antiserum plus complement resulted in the elimination of helper activity for B-cell responses to trinitrophenyl-KLH. Inhibition was shown to be a result of the selective killing of one type of helper T cell whose activity could be replaced by a factor(s) found in the supernate of Con A-activated spleen cells. A second type of helper cell required for responses to protein-bound antigens appeared to be Ia-. By absorption and analysis on H-2 recombinants, at least two specificities were detectable on helper T cells; one mapping in the I-A subregion and a second in a region(s) to the right of I-J. In addition, the helper T cell(s) involved in the generation of alloreactive cytotoxic lymphocytes was shown to be Ia+, whereas cytotoxic effector cells and their precursors were Ia- with this antiserum. These results provide strong evidence for the selective expression of I-region determinants on T-cell subsets and suggest that T-cell-associated Ia antigens may play an important role in T-lymphocyte function.

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