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.

Paradoxic inhibition of human natural interferon-producing cells by the activating receptor NKp44

Blood ◽  
2005 ◽  
Vol 106 (6) ◽  
pp. 2076-2082 ◽  
Author(s):  
Anja Fuchs ◽  
Marina Cella ◽  
Takayuki Kondo ◽  
Marco Colonna
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Close Contact ◽  
Killer Cell ◽  
Adaptor Protein ◽  
Interferon Α ◽  
Memory Cd8 T Cells ◽  
Activating Receptor

Abstract Natural killer (NK) cell-mediated cytotoxicity is triggered by multiple activating receptors associated with the signaling adaptor protein DNAX activation protein 12/killer cell-activating receptor-associated protein (DAP12/KARAP). Here, we show that one of these receptors, NKp44, is present on a subset of natural interferon-producing cells (IPCs) in tonsils. NKp44 expression can also be induced on blood IPCs after in vitro culture with interleukin 3 (IL-3). Crosslinking of NKp44 does not trigger IPC-mediated cytotoxicity but, paradoxically, inhibits interferon α (IFN-α) production by IPCs in response to cytosine-phosphate-guanosine (CpG) oligonucleotides. We find that IPCs in tonsils are in close contact with CD8+ T cells and demonstrate that a subset of memory CD8+ T cells produces IL-3. Therefore, IL-3-mediated induction of NKp44 on IPCs may be an important component of the ongoing crosstalk between the innate and adaptive immune response that allows memory CD8+ T cells to control the IPC response to virus. (Blood. 2005;106: 2076-2082)

scholarly journals Transient and persistent effects of IL-15 on lymphocyte homeostasis in nonhuman primates

Blood ◽  
2010 ◽  
Vol 116 (17) ◽  
pp. 3238-3248 ◽  
Author(s):  
Enrico Lugli ◽  
Carolyn K. Goldman ◽  
Liyanage P. Perera ◽  
Jeremy Smedley ◽  
Rhonda Pung ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Nk Cell ◽  
The Body ◽  
Effector Memory ◽  
Memory Cd8 T Cells

Abstract Interleukin-15 (IL-15) is a cytokine with potential therapeutic application in individuals with cancer or immunodeficiency to promote natural killer (NK)– and T-cell activation and proliferation or in vaccination protocols to generate long-lived memory T cells. Here we report that 10-50 μg/kg IL-15 administered intravenously daily for 12 days to rhesus macaques has both short- and long-lasting effects on T-cell homeostasis. Peripheral blood lymphopenia preceded a dramatic expansion of NK cells and memory CD8 T cells in the circulation, particularly a 4-fold expansion of central memory CD8 T cells and a 6-fold expansion of effector memory CD8 T cells. This expansion is a consequence of their activation in multiple tissues. A concomitant inverted CD4/CD8 T-cell ratio was observed throughout the body at day 13, a result of preferential CD8 expansion. Expanded T- and NK-cell populations declined in the blood soon after IL-15 was stopped, suggesting migration to extralymphoid sites. By day 48, homeostasis appears restored throughout the body, with the exception of the maintenance of an inverted CD4/CD8 ratio in lymph nodes. Thus, IL-15 generates a dramatic expansion of short-lived memory CD8 T cells and NK cells in immunocompetent macaques and has long-term effects on the balance of CD4+ and CD8+ T cells.

scholarly journals Expansion of CD8+ T cells lacking Sema4D/CD100 during HIV-1 infection identifies a subset of T cells with decreased functional capacity

Blood ◽  
2012 ◽  
Vol 119 (3) ◽  
pp. 745-755 ◽  
Author(s):  
Emily M. Eriksson ◽  
Jeffrey M. Milush ◽  
Emily L. Ho ◽  
Mariana D. Batista ◽  
Sara J. Holditch ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Costimulatory Molecule ◽  
Absolute Number ◽  
Elite Controllers ◽  
Effector Cells ◽  
Specific Priming ◽  
Hiv 1

AbstractSema4D, also known as CD100, is a constitutively expressed immune semaphorin on T cells and NK cells. CD100 has important immune regulatory functions that improve antigen-specific priming by antigen-presenting cells, and can also act as a costimulatory molecule on T cells. We investigated the consequence of HIV-1 infection on CD100 expression by T cells, and whether CD100 expression signifies functionally competent effector cells. CD100 expression on T cells from healthy individuals was compared with HIV-1–infected subjects including elite controllers, noncontrollers, and patients receiving antiretroviral therapy. The frequency and fluorescence intensity of CD100 on CD8+ and CD4+ T cells were decreased during HIV-1 infection. Furthermore, the absolute number of CD100-expressing CD8+ T cells was positively associated with the magnitude of HIV-1–specific T-cell responses. CD8+ T cells lacking CD100 expression were functionally impaired and present in increased numbers in HIV-1–infected individuals. The number of CD100−CD8+ T cells positively correlated with T-cell immunosenescence, immune activation, and viral load. Loss of CD100 expression appears to result from direct antigen stimulation, as in vitro cytokine exposure and viral replication did not significantly impact CD100 expression. These data suggest that loss of CD100 expression probably plays an important role in dysfunctional immunity in HIV-1 infection.

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 The Role of ZEB2 in Human CD8 T Lymphocytes: Clinical and Cellular Immune Profiling in Mowat–Wilson Syndrome

2021 ◽  
Vol 22 (10) ◽  
pp. 5324
Author(s):  
Katie Frith ◽  
C. Mee Ling Munier ◽  
Lucy Hastings ◽  
David Mowat ◽  
Meredith Wilson ◽  
...  
Keyword(s):  
T Cells ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Oral Candidiasis ◽  
Expression Patterns ◽  
Cell Subset ◽  
Effector Memory ◽  
Healthy Human

The Zeb2 gene encodes a transcription factor (ZEB2) that acts as an important immune mediator in mice, where it is expressed in early-activated effector CD8 T cells, and limits effector differentiation. Zeb2 homozygous knockout mice have deficits in CD8 T cells and NK cells. Mowat–Wilson syndrome (MWS) is a rare genetic disease resulting from heterozygous mutations in ZEB2 causing disease by haploinsufficiency. Whether ZEB2 exhibits similar expression patterns in human CD8 T cells is unknown, and MWS patients have not been comprehensively studied to identify changes in CD8 lymphocytes and NK cells, or manifestations of immunodeficiency. By using transcriptomic assessment, we demonstrated that ZEB2 is expressed in early-activated effector CD8 T cells of healthy human volunteers following vaccinia inoculation and found evidence of a role for TGFß-1/SMAD signaling in these cells. A broad immunological assessment of six genetically diagnosed MWS patients identified two patients with a history of recurrent sinopulmonary infections, one of whom had recurrent oral candidiasis, one with lymphopenia, two with thrombocytopenia and three with detectable anti-nuclear antibodies. Immunoglobulin levels, including functional antibody responses to protein and polysaccharide vaccination, were normal. The MWS patients had a significantly lower CD8 T cell subset as % of lymphocytes, compared to healthy controls (median 16.4% vs. 25%, p = 0.0048), and resulting increased CD4:CD8 ratio (2.6 vs. 1.8; p = 0.038). CD8 T cells responded normally to mitogen stimulation in vitro and memory CD8 T cells exhibited normal proportions of subsets with important tissue-specific homing markers and cytotoxic effector molecules. There was a trend towards a decrease in the CD8 T effector memory subset (3.3% vs. 5.9%; p = 0.19). NK cell subsets were normal. This is the first evidence that ZEB2 is expressed in early-activated human effector CD8 T cells, and that haploinsufficiency of ZEB2 in MWS patients had a slight effect on immune function, skewing T cells away from CD8 differentiation. To date there is insufficient evidence to support an immunodeficiency occurring in MWS patients.

scholarly journals IL-15 induces antigen-independent expansion and differentiation of human naive CD8+ T cells in vitro

Blood ◽  
2003 ◽  
Vol 102 (7) ◽  
pp. 2541-2546 ◽  
Author(s):  
Nuno L. Alves ◽  
Berend Hooibrink ◽  
Fernando A. Arosa ◽  
René A. W. van Lier
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Interferon Γ ◽  
T Cell Subsets ◽  
Memory Cd8 T Cells ◽  
Effector Cells ◽  
Independent Expansion

Abstract Recent studies in mice have shown that although interleukin 15 (IL-15) plays an important role in regulating homeostasis of memory CD8+ T cells, it has no apparent function in controlling homeostatic proliferation of naive T cells. We here assessed the influence of IL-15 on antigen-independent expansion and differentiation of human CD8+ T cells. Both naive and primed human T cells divided in response to IL-15. In this process, naive CD8+ T cells successively down-regulated CD45RA and CD28 but maintained CD27 expression. Concomitant with these phenotypic changes, naive cells acquired the ability to produce interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α), expressed perforin and granzyme B, and acquired cytotoxic properties. Primed CD8+ T cells, from both noncytotoxic (CD45RA-CD27+) and cytotoxic (CD45RA+CD27-) subsets, responded to IL-15 and yielded ample numbers of cytokine-secreting and cytotoxic effector cells. In summary, all human CD8+ T-cell subsets had the ability to respond to IL-15, which suggests a generic influence of this cytokine on CD8+ T-cell homeostasis in man. (Blood. 2003;102:2541-2546)

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 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.

scholarly journals Human effector CD8+ T cells derived from naive rather than memory subsets possess superior traits for adoptive immunotherapy

Blood ◽  
2011 ◽  
Vol 117 (3) ◽  
pp. 808-814 ◽  
Author(s):  
Christian S. Hinrichs ◽  
Zachary A. Borman ◽  
Luca Gattinoni ◽  
Zhiya Yu ◽  
William R. Burns ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Adoptive Immunotherapy ◽  
Killer Cell ◽  
Terminal Differentiation ◽  
Genetically Engineered ◽  
Effector Memory ◽  
Proliferative Potential ◽  
Effector Cells

Abstract Cluster of differentiation (CD)8+ T cells exist as naive, central memory, and effector memory subsets, and any of these populations can be genetically engineered into tumor-reactive effector cells for adoptive immunotherapy. However, the optimal subset from which to derive effector CD8+ T cells for patient treatments is controversial and understudied. We investigated human CD8+ T cells and found that naive cells were not only the most abundant subset but also the population most capable of in vitro expansion and T-cell receptor transgene expression. Despite increased expansion, naive-derived cells displayed minimal effector differentiation, a quality associated with greater efficacy after cell infusion. Similarly, the markers of terminal differentiation, killer cell lectin-like receptor G1 and CD57, were expressed at lower levels in cells of naive origin. Finally, naive-derived effector cells expressed higher CD27 and retained longer telomeres, characteristics that suggest greater proliferative potential and that have been linked to greater efficacy in clinical trials. Thus, these data suggest that naive cells resist terminal differentiation, or “exhaustion,” maintain high replicative potential, and therefore may be the superior subset for use in adoptive immunotherapy.

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