scholarly journals Distinct Profiles of Cytotoxic Granules in Memory CD8 T Cells Correlate with Function, Differentiation Stage, and Antigen Exposure

2009 ◽  
Vol 83 (7) ◽  
pp. 2862-2871 ◽  
Author(s):  
Alexandre Harari ◽  
Felicitas Bellutti Enders ◽  
Cristina Cellerai ◽  
Pierre-Alexandre Bart ◽  
Giuseppe Pantaleo
Keyword(s):  
T Cells ◽  
Influenza Virus ◽  
Cd8 T Cells ◽  
Early Stage ◽  
Intermediate Stage ◽  
Memory Cd8 T Cells ◽  
Differentiation Stage ◽  
Hiv 1

ABSTRACT Cytotoxic CD8 T cells exert their antiviral and antitumor activity primarily through the secretion of cytotoxic granules. Degranulation activity and cytotoxic granules (perforin plus granzymes) generally define CD8 T cells with cytotoxic function. In this study, we have investigated the expression of granzyme K (GrmK) in comparison to that of GrmA, GrmB, and perforin. The expression of the cytotoxic granules was assessed in virus-specific CD8 T cells specific to influenza virus, Epstein-Barr virus (EBV), cytomegalovirus (CMV), or human immunodeficiency virus type 1 (HIV-1). We observed a dichotomy between GrmK and perforin expression in virus-specific CD8 T cells. The profile in influenza virus-specific CD8 T cells was perforin− GrmB− GrmA+/− GrmK+; in CMV-specific cells, it was perforin+ GrmB+ GrmA+ GrmK−/+; and in EBV- and HIV-1-specific cells, it was perforin−/+ GrmB+ GrmA+ GrmK+. On the basis of the delineation of memory and effector CD8 T cells with CD45RA and CD127, the GrmK+ profile was associated with early-stage memory CD8 T-cell differentiation, the perforin+ GrmB+ GrmA+ profile with advanced-stage differentiation, and the GrmB+ GrmA+ Grmk+ profile with intermediate-stage differentiation. Furthermore, perforin and GrmB but not GrmA and GrmK correlated with cytotoxic activity. Finally, changes in antigen exposure in vitro and in vivo during primary HIV-1 infection and vaccination modulated cytotoxic granule profiles. These results advance our understanding of the relationship between distinct profiles of cytotoxic granules in memory CD8 T cells and function, differentiation stage, and antigen exposure.

scholarly journals Human memory CD8 T cell effector potential is epigenetically preserved during in vivo homeostasis

2017 ◽  
Vol 214 (6) ◽  
pp. 1593-1606 ◽  
Author(s):  
Hossam A. Abdelsamed ◽  
Ardiana Moustaki ◽  
Yiping Fan ◽  
Pranay Dogra ◽  
Hazem E. Ghoneim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Human Memory ◽  
Memory Cd8 T Cells ◽  
Memory Cd8 T Cell ◽  
Cell Effector

Antigen-independent homeostasis of memory CD8 T cells is vital for sustaining long-lived T cell–mediated immunity. In this study, we report that maintenance of human memory CD8 T cell effector potential during in vitro and in vivo homeostatic proliferation is coupled to preservation of acquired DNA methylation programs. Whole-genome bisulfite sequencing of primary human naive, short-lived effector memory (TEM), and longer-lived central memory (TCM) and stem cell memory (TSCM) CD8 T cells identified effector molecules with demethylated promoters and poised for expression. Effector-loci demethylation was heritably preserved during IL-7– and IL-15–mediated in vitro cell proliferation. Conversely, cytokine-driven proliferation of TCM and TSCM memory cells resulted in phenotypic conversion into TEM cells and was coupled to increased methylation of the CCR7 and Tcf7 loci. Furthermore, haploidentical donor memory CD8 T cells undergoing in vivo proliferation in lymphodepleted recipients also maintained their effector-associated demethylated status but acquired TEM-associated programs. These data demonstrate that effector-associated epigenetic programs are preserved during cytokine-driven subset interconversion of human memory CD8 T cells.

scholarly journals Delineation of antigen-specific and antigen-nonspecific CD8+ memory T-cell responses after cytokine-based cancer immunotherapy

Blood ◽  
2012 ◽  
Vol 119 (13) ◽  
pp. 3073-3083 ◽  
Author(s):  
Julia K. Tietze ◽  
Danice E. C. Wilkins ◽  
Gail D. Sckisel ◽  
Myriam N. Bouchlaka ◽  
Kory L. Alderson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Human Memory ◽  
Antigen Specificity ◽  
Antitumor Effects ◽  
Memory Cd8 T Cells ◽  
Specific Tumor

Abstract Memory T cells exhibit tremendous antigen specificity within the immune system and accumulate with age. Our studies reveal an antigen-independent expansion of memory, but not naive, CD8+ T cells after several immunotherapeutic regimens for cancer resulting in a distinctive phenotype. Signaling through T-cell receptors (TCRs) or CD3 in both mouse and human memory CD8+ T cells markedly up-regulated programmed death-1 (PD-1) and CD25 (IL-2 receptor α chain), and led to antigen-specific tumor cell killing. In contrast, exposure to cytokine alone in vitro or with immunotherapy in vivo did not up-regulate these markers but resulted in expanded memory CD8+ T cells expressing NKG2D, granzyme B, and possessing broadly lytic capabilities. Blockade of NKG2D in mice also resulted in significantly diminished antitumor effects after immunotherapy. Treatment of TCR-transgenic mice bearing nonantigen expressing tumors with immunotherapy still resulted in significant antitumor effects. Human melanoma tissue biopsies obtained from patients after topically applied immunodulatory treatment resulted in increased numbers of these CD8+ CD25− cells within the tumor site. These findings demonstrate that memory CD8+ T cells can express differential phenotypes indicative of adaptive or innate effectors based on the nature of the stimuli in a process conserved across species.

scholarly journals Platelets are dispensable for the ability of CD8+ T cells to accumulate, patrol, kill and reside in the liver

2021 ◽  
Author(s):  
James H O'Connor ◽  
Hayley A McNamara ◽  
Yeping Cai ◽  
Lucy A Coupland ◽  
Elizabeth E Gardiner ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Protective Function ◽  
Memory Cd8 T Cells ◽  
Effector Cells ◽  
Large Numbers ◽  
Platelet Concentration

Effector and memory CD8+ T cells accumulate in large numbers in the liver where they play key roles in the control of liver pathogens including Plasmodium. It has also been proposed that liver may act as the main place for elimination of effector CD8+ T cells at the resolution of immune responses. Platelets and the integrin LFA-1 have been proposed to be critical for the accumulation of protective CD8+ T cells in the liver; conversely, asialo-glycoprotein (ASGP) expression on the surface of CD8+ T cells has been proposed to assist in elimination of effector T cells in the liver. Here we investigated the contributions of these interactions in the accumulation of CD8+ T cells activated in vitro or in vivo by immunization with Plasmodium parasites. Using Mpl-/- mice with constitutive thrombocytopaenia and antibody-mediated platelet depletion models we found that severe reduction in platelet concentration in circulation did not strongly influence the accumulation and protective function of CD8+ T cells in the liver in these models. Surprisingly, inhibition of ASGP receptors did not inhibit the accumulation of effector cells in the liver, but instead prevented these cells from accumulating in the spleen. We further found that enforced expression of ASGP on effector CD8+ T cells using St3GalI knockout cells lead to their loss from the spleen. These data suggest that platelets play a marginal role in CD8+ T cell function in the liver. Furthermore, ASGP-expressing effector CD8+ T cells are retained in the liver but are lost from the spleen.

scholarly journals ART duration and immunometabolic state determine efficacy of DC-based treatment restoring functional HIV- specific CD8+ T cells in Chronic PLWH.

2022 ◽  
Author(s):  
Marta Calvet-Mirabent ◽  
Ildefonso Sanchez-Cerrillo ◽  
Noa Martin-Cofreces ◽  
Hortensia De La Fuente ◽  
Ilya Tsukalov ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Functional Restoration ◽  
Functional Improvement ◽  
People Living With Hiv ◽  
Memory Cd8 T Cells ◽  
Metabolic States ◽  
Hiv 1

Dysfunction of CD8+ T cells in people living with HIV-1 (PLWH) receiving anti-retroviral therapy (ART) has restricted the efficacy of dendritic cell (DC)-based immunotherapies against HIV-1. Heterogeneous immune exhaustion and metabolic states of CD8+ T cells might differentially associate with dysfunction. However, specific parameters associated to functional restoration of CD8+ T cells after DC treatment have not been investigated in detail. Here, we studied the association of ART duration with memory subsets, exhaustion and metabolic profiles of CD8+ T cells from PLWH and improvement of polyfunctional and effector HIV-1 specific responses after stimulation with Gag-adjuvant-primed DC. HIV-1-specific CD8+ T cell responses from a larger proportion PLWH on ART for more than 10 years (LT-ARTp) improved polyfunctionality and capacity to eliminate autologous p24+ infected CD4+ T cells in vitro. In contrast, CD8+ T cells from PLWH on ART for less than a decade (ST-ARTp) were less responsive to DC treatment and functional improvement was limited in this group. This was associated with lower frequencies of central memory CD8+ T cells, increased co-expression of PD1 and TIGIT and reduced mitochondrial respiration and glycolytic induction upon TCR activation. In contrast, CD8+ T cells from LT-ARTp showed increased frequencies of TIM3+PD1- cells and preserved induction of glycolysis. Treatment of dysfunctional CD8+ T cells from ST-ARTp with combined anti-PD1 and anti-TIGIT antibodies plus a glycolysis promoting drug restored their ability to eliminate infected CD4+ T cells. Together, our study identifies specific immunometabolic parameters for different PLWH subgroups potentially useful for future personalized DC-based HIV-1 vaccines.

scholarly journals GZMKhigh CD8+ T effector memory cells are associated with CD15high neutrophil abundance in early-stage colorectal tumors and predict poor clinical outcome.

2021 ◽  
Author(s):  
Silvia Tiberti ◽  
Carlotta Catozzi ◽  
Caterina Scirgolea ◽  
Ottavio Croci ◽  
Mattia Ballerini ◽  
...  
Keyword(s):  
T Cells ◽  
Clinical Outcome ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Early Stage ◽  
Effector Memory ◽  
Functional Changes

Tumor contexture has emerged as a major determinant to establish prognosis and guide novel therapies and tumor infiltrating CD8+ T cells have been associated with a better prognosis in several solid tumors, including early-stage colorectal cancer (CRC). However, the tumor immune infiltrate is highly heterogeneous and understanding how the interplay between different immune cell compartments impacts on the clinical outcome is still in its infancy. Here, we describe in a prospective cohort a novel CD8+ T effector memory population, which is characterized by high levels of Granzyme K (GZMKhigh CD8+ TEM) and correlated with CD15high tumor infiltrating neutrophils. We provide both in vitro and in vivo evidence of the role of stromal cell-derived factor 1 (CXCL12/SDF-1) in driving functional changes on neutrophils at the tumor site, promoting their retention and increasing crosstalk with CD8+ T cells. Mechanistically, as a consequence of the interaction with neutrophils, CD8+ T cells are skewed towards a CD8+ TEM phenotype, producing high levels of GZMK, which in turn decreased E-cadherin pathway. The correlation of GZMKhigh CD8+ TEM and neutrophils with both tumor progression in mice and early relapse in CRC patients demonstrate the role of GZMKhigh CD8+ TEM in promoting malignancy. Indeed, a gene signature defining GZMKhigh CD8+ TEM was associated with worse prognosis on a larger independent cohort of CRC patients and a similar analysis was extended to lung cancer (TCGA). Overall, our results highlight the emergence of GZMKhigh CD8+ TEM in early-stage CRC tumors as a hallmark driven by the interaction with neutrophils, which could implement current patient stratification and be targeted by novel therapeutics.

FcRL6, a new ITIM-bearing receptor on cytolytic cells, is broadly expressed by lymphocytes following HIV-1 infection

Blood ◽  
2007 ◽  
Vol 109 (9) ◽  
pp. 3786-3793 ◽  
Author(s):  
Timothy J. Wilson ◽  
Rachel M. Presti ◽  
Ilaria Tassi ◽  
Edgar T. Overton ◽  
Marina Cella ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Fc Receptor ◽  
Effector Memory ◽  
Minimal Impact ◽  
Memory Cd8 T Cells ◽  
Effector Cells ◽  
Hiv 1

Abstract Fc receptor–like proteins (FcRLs) are a growing family of molecules homologous to FcγRI. Whereas all 7 previously reported Fc receptor homologs are expressed by B cells, here we report a new receptor, FcRL6, that is expressed by cytolytic cells including natural killer (NK) cells and effector and effector-memory CD8+ T cells. FcRL6 contains a novel cytoplasmic cysteine-rich motif and recruits SHP-2 through a phosphorylated ITIM, indicating a potential signaling function in effector lymphocytes. In vitro, FcRL6 does not greatly influence NK-cell or CD8+ T-cell–mediated cytotoxicity and has minimal impact on cytokine secretion. However, FcRL6 expression among T lymphocytes is greatly expanded in human immunodeficiency virus type 1 (HIV-1)–infected individuals, and includes not only effector and effector-memory CD8+ T cells but also populations of CD4+ T cells. Expansion of FcRL6-positive lymphocytes is not related to viral load, but is indicative of the dysregulated expansion of terminally differentiated effector lymphocyte populations in response to chronic HIV-1 infection and may serve as an important marker for chronic immune activation and for tracking the generation of effector cells following immune stimulation.

scholarly journals Programming tumor-reactive effector memory CD8+ T cells in vitro obviates the requirement for in vivo vaccination

Blood ◽  
2009 ◽  
Vol 114 (9) ◽  
pp. 1776-1783 ◽  
Author(s):  
Christopher A. Klebanoff ◽  
Zhiya Yu ◽  
Leroy N. Hwang ◽  
Douglas C. Palmer ◽  
Luca Gattinoni ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cell Receptor ◽  
Adoptive Cell Transfer ◽  
Effector Memory ◽  
Cell Transfer ◽  
Memory Cd8 T Cells ◽  
Ifn Γ

Abstract Naive and memory CD8+ T cells can undergo programmed activation and expansion in response to a short T-cell receptor stimulus, but the extent to which in vitro programming can qualitatively substitute for an in vivo antigen stimulation remains unknown. We show that self-/tumor-reactive effector memory CD8+ T cells (TEM) programmed in vitro either with peptide-pulsed antigen-presenting cells or plate-bound anti-CD3/anti-CD28 embark on a highly stereotyped response of in vivo clonal expansion and tumor destruction nearly identical to that of vaccine-stimulated TEM cells. This programmed response was associated with an interval of antigen-independent interferon-γ (IFN-γ) release that facilitated the dynamic expression of the major histocompatibility complex class I restriction element H-2Db on responding tumor cells, leading to recognition and subsequent tumor lysis. Delaying cell transfer for more than 24 hours after stimulation or infusion of cells deficient in IFN-γ entirely abrogated the benefit of the programmed response, whereas transfer of cells unable to respond to IFN-γ had no detriment to antitumor immunity. These findings extend the phenomenon of a programmable effector response to memory CD8+ T cells and have major implications for the design of current adoptive-cell transfer trials.

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