Effector/memory T cells of the weanling mouse exhibit Type 2 cytokine polarization in vitro and in vivo in the advanced stages of acute energy deficit

Abstract Natural killer (NK) cells have been originally defined by their “naturally occurring” effector function. However, only a fraction of human NK cells is reactive toward a panel of prototypical tumor cell targets in vitro, both for the production of interferon-γ (IFN-γ) and for their cytotoxic response. In patients with IL12RB1 mutations that lead to a complete IL-12Rβ1 deficiency, the size of this naturally reactive NK cell subset is diminished, in particular for the IFN-γ production. Similar data were obtained from a patient with a complete deficit in IL-12p40. In addition, the size of the subset of effector memory T cells expressing CD56 was severely decreased in IL-12Rβ1– and IL-12p40–deficient patients. Human NK cells thus require in vivo priming with IL-12/23 to acquire their full spectrum of functional reactivity, while T cells are dependent upon IL-12/23 signals for the differentiation and/or the maintenance of CD56+ effector memory T cells. The susceptibility of IL-12/23 axis–deficient patients to Mycobacterium and Salmonella infections in combination with the absence of mycobacteriosis or salmonellosis in the rare cases of human NK cell deficiencies point to a role for CD56+ T cells in the control of these infections in humans.

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Elevated circulating effector memory T cells but similar levels of regulatory T cells in patients with type 2 diabetes mellitus and cardiovascular disease

Diabetes and Vascular Disease Research ◽

10.1177/1479164118817942 ◽

2018 ◽

Vol 16 (3) ◽

pp. 270-280 ◽

Cited By ~ 9

Author(s):

Sara Rattik ◽

Daniel Engelbertsen ◽

Maria Wigren ◽

Irena Ljungcrantz ◽

Gerd Östling ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Cardiovascular Disease ◽

T Cells ◽

Type 2 Diabetes Mellitus ◽

Regulatory T Cells ◽

Memory T Cells ◽

Effector Memory ◽

Effector Memory T Cells

Type 2 diabetes mellitus is associated with an elevated risk of cardiovascular disease, but the mechanism through which diabetes contributes to cardiovascular disease development remains incompletely understood. In this study, we compared the association of circulating regulatory T cells, naïve T cells, effector memory T cells or central memory T cells with cardiovascular disease in patients with and without type 2 diabetes mellitus. Percentage of circulating T cell subsets was analysed by flow cytometry in type 2 diabetes mellitus subjects with and without prevalent cardiovascular disease as well as in non-diabetic subjects with and without prevalent cardiovascular disease from the Malmö SUMMIT cohort. Subjects with type 2 diabetes mellitus had elevated percentages of effector memory T cells (CD4+CD45RO+CD62L–; 21.8% ± 11.2% vs 17.0% ± 9.2% in non-type 2 diabetes mellitus, p < 0.01) and central memory T cells (CD4+CD45RO+CD62L+; 38.0% ± 10.7% vs 36.0% ± 9.5% in non-type 2 diabetes mellitus, p < 0.01). In contrast, the frequency of naïve T cells was reduced (CD4+CD45RO–CD62L+, 35.0% ± 16.5% vs 42.9% ± 14.4% in non-type 2 diabetes mellitus, p < 0.001). The proportion of effector memory T cells was increased in type 2 diabetes mellitus subjects with cardiovascular disease as compared to those without (26.4% ± 11.5% vs 18.4% ± 10.2%, p < 0.05), while no difference in regulatory T cells was observed between these two patient groups. This study identifies effector memory T cells as a potential cellular biomarker for cardiovascular disease among subjects with type 2 diabetes mellitus, suggesting a state of exacerbated immune activation in type 2 diabetes mellitus patients with cardiovascular disease.

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Lineage relationships, homeostasis, and recall capacities of central– and effector–memory CD8 T cells in vivo

Journal of Experimental Medicine ◽

10.1084/jem.20040876 ◽

2005 ◽

Vol 201 (4) ◽

pp. 579-590 ◽

Cited By ~ 108

Author(s):

Cécile Bouneaud ◽

Zacarias Garcia ◽

Philippe Kourilsky ◽

Christophe Pannetier

Keyword(s):

T Cells ◽

Memory T Cells ◽

Cell Receptor ◽

Effector Memory ◽

Memory Cd8 T Cells ◽

Receptor Repertoire ◽

Effector Memory T Cells ◽

Secondary Challenge ◽

Short Time

The lineage relationships of central–memory T cells (TCM) cells and effector–memory T cells (TEM), as well as their homeostasis and recall capacities, are still controversial. We investigated these issues in a murine model using two complementary approaches: T cell receptor repertoire analysis and adoptive transfer experiments of purified H-Y–specific TCM and TEM populations. Repertoire studies showed that approximately two thirds of TCM and TEM clones derived from a common naive precursor, whereas the other third was distinct. Both approaches highlighted that TCM and TEM had drastically distinct behaviors in vivo, both in the absence of antigen or upon restimulation. TCM clones were stable in the absence of restimulation and mounted a potent and sustained recall response upon secondary challenge, giving rise to both TCM and TEM, although only a fraction of TCM generated TEM. In contrast, TEM persisted for only a short time in the absence of antigen and, although a fraction of them were able to express CD62L, they were unable to mount a proliferative response upon secondary challenge in this model.

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IL-15 Augments in-Vitro Expansion and Functional Activity of Antigen-Specific Effector Memory T-Cells (TEM) While Co-Expression of IL-15 and IL-15 Rα on Antigen Presenting Cells Also Promotes Expansion of Central Memory T-Cells (TCM)

Blood ◽

10.1182/blood.v112.11.3541.3541 ◽

2008 ◽

Vol 112 (11) ◽

pp. 3541-3541

Author(s):

Aisha Hasan ◽

Annamalai Selvakumar ◽

Bo Dupont ◽

Michel Sadelain ◽

Isabelle Riviere ◽

...

Keyword(s):

T Cells ◽

Cytotoxic Activity ◽

Memory T Cells ◽

Antigen Presenting Cells ◽

Effector Memory ◽

Central Memory T Cells ◽

Receptor Alpha ◽

Antigen Presenting

Abstract Adoptive immunotherapy with in-vitro expanded antigen-specific T cells (TC) is often hampered by the extended culture times required to generate sufficient numbers of antigen- specific TC and their limited persistence in-vivo. IL-2 predominantly supports the generation of short-lived effector memory (TEM) and effector (TE) CD8+ TC without expanding the CD62L+ and CCR7+ central memory T cells (TCM), which may persist for long periods in vivo. We examined the potential of IL-15 to foster growth of CMVpp65- specific TC as well as expansion of both TEM and TCM CD8+ TC. Accordingly, TC from 3 seropositive donors bearing HLA A0201 were sensitized in-vitro using NIH 3T3 based artificial antigen presenting cells transduced to express B7.1, ICAM-1, LFA-3, β2-M and HLA A0201 heavy chain as well as CMVpp65 (A2-AAPC) in presence of exogenous IL-2, IL-15 or IL-15 plus IL-2. To assess if trans-presentation of IL-15 by the receptor alpha on AAPCs leads to enhancement of IL-15 activity, we sequentially transduced A2-AAPCs with the IL-15 and IL-15 receptor alpha cDNA (A2- AAPC IL-15/IL-15Rα). TC were then cultured using A2-AAPC with either IL-2 (20U/ml) IL-15 (10ng/ml) IL-2 plus IL-15 or with A2-AAPC IL-15/IL-15Rα or A2-AAPC IL-15Rα + IL-2 (20U/ml). TC sensitized using either A2-AAPC IL-15/IL-15Rα or A2-AAPC + IL-15 demonstrated ~ 1500–2000 fold expansion of CMVpp65 A2-NLV tetramer (+) CD8+ TC, compared to a 300–600 fold expansion using A2-AAPC + IL-2 after 21–28 days in culture. Cultures containing IL-15 generated 25–70 ×106 A2-NLV tetramer (+) CD8+ TC in comparison to 10–18 ×106 in cultures with IL-2. At 7–10 days, ~20% of the tetramer (+) TC demonstrated a TCM phenotype (CD62L+ and CCR7+) in all cultures, with 75% TEM and 5% TE. By 21- 28 days, no TCM were detected among tetramer (+) TC in cultures containing exogenous IL-2, IL-15 or IL-2 plus IL-15. However, TC sensitized with A2-AAPC IL-15/IL-15Rα still contained 10–12% (~7×106) tetramer (+) CD8+ TCM which further increased through day 35. In functional assays, TC sensitized in the presence of IL-15 or AAPCs expressing IL-15 and IL-15Rα elicited superior CMV-specific responses with 7–20% CD8+ TC demonstrating CMVpp65 epitope specific interferon gamma production compared to 2–3% in cultures with IL-2. Cytotoxic activity against CMV pp65 peptide loaded autologous EBV transformed B-cell lines (E:T= 10:1) was higher for TC sensitized with IL-15 (80%) compared to cultures with IL-2 (60%). The cytotoxic activity against HLA mismatched targets or K562 was <5% in all cultures. In conclusion, our data demonstrate higher yields and augmented function in antigen specific T cells cultured with IL-15. TC sensitized with A2-AAPC-CMVpp65 together with IL-15 +/− IL-2 only supported sustained expansion of TEM and TE. In contrast, TC sensitized with A2-AAPC IL-15/IL-15Rα also supported sustained expansion of TCM.

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Siplizumab selectively depletes effector memory T cells and promotes a relative expansion of alloreactive regulatory T cells in vitro

American Journal of Transplantation ◽

10.1111/ajt.15533 ◽

2019 ◽

Vol 20 (1) ◽

pp. 88-100 ◽

Cited By ~ 5

Author(s):

Manuel A. Podestà ◽

Christian Binder ◽

Felix Sellberg ◽

Susan DeWolf ◽

Brittany Shonts ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Memory T Cells ◽

Effector Memory ◽

Effector Memory T Cells ◽

Relative Expansion

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Conversion of antigen-specific effector/memory T cells into Foxp3-expressing Treg cells by inhibition of CDK8/19

Science Immunology ◽

10.1126/sciimmunol.aaw2707 ◽

2019 ◽

Vol 4 (40) ◽

pp. eaaw2707 ◽

Cited By ~ 19

Author(s):

Masahiko Akamatsu ◽

Norihisa Mikami ◽

Naganari Ohkura ◽

Ryoji Kawakami ◽

Yohko Kitagawa ◽

...

Keyword(s):

T Cells ◽

Autoimmune Disease ◽

Cell Function ◽

Memory T Cells ◽

Contact Hypersensitivity ◽

Effector Memory ◽

Skin Contact ◽

Effector Memory T Cells ◽

Specific Effector

A promising way to restrain hazardous immune responses, such as autoimmune disease and allergy, is to convert disease-mediating T cells into immunosuppressive regulatory T (Treg) cells. Here, we show that chemical inhibition of the cyclin-dependent kinase 8 (CDK8) and CDK19, or knockdown/knockout of the CDK8 or CDK19 gene, is able to induce Foxp3, a key transcription factor controlling Treg cell function, in antigen-stimulated effector/memory as well as naïve CD4+ and CD8+ T cells. The induction was associated with STAT5 activation, independent of TGF-β action, and not affected by inflammatory cytokines. Furthermore, in vivo administration of a newly developed CDK8/19 inhibitor along with antigen immunization generated functionally stable antigen-specific Foxp3+ Treg cells, which effectively suppressed skin contact hypersensitivity and autoimmune disease in animal models. The results indicate that CDK8/19 is physiologically repressing Foxp3 expression in activated conventional T cells and that its pharmacological inhibition enables conversion of antigen-specific effector/memory T cells into Foxp3+ Treg cells for the treatment of various immunological diseases.

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IN-VIVO FUNCTION DISTINGUISHES ALLOREACTIVE CD8 CENTRAL AND EFFECTOR MEMORY T CELLS.

Transplantation Journal ◽

10.1097/00007890-200607152-00563 ◽

2006 ◽

Vol 82 (Suppl 2) ◽

pp. 255-256

Author(s):

&NA;

Keyword(s):

T Cells ◽

Memory T Cells ◽

Effector Memory ◽

Effector Memory T Cells

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Clonal expansion and TCR-independent differentiation shape the HIV-specific CD8+ effector-memory T-cell repertoire in vivo

Blood ◽

10.1182/blood-2009-11-254136 ◽

2010 ◽

Vol 116 (3) ◽

pp. 396-405 ◽

Cited By ~ 17

Author(s):

Dirk Meyer-Olson ◽

Brenna C. Simons ◽

Joseph A. Conrad ◽

Rita M. Smith ◽

Louise Barnett ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Memory T Cells ◽

Significant Proportion ◽

Clonal Expansion ◽

Effector Memory ◽

Structural Constraints ◽

Effector Memory T Cells ◽

Hiv 1

AbstractFlexibility of the HIV-specific T-cell receptor repertoire is a hallmark of HIV-1 infection. Altered differentiation of HIV-specific CD45RO+/CCR7− (TemRO) CD8+ effector-memory T cells into CD45RA+/CCR7− (TemRA) CD8+ effector-memory T cells as well as increased expression of the senescence marker CD57 has been frequently observed HIV-1 infection, but the structural relationship between clonal expansion and T-cell differentiation has not been defined. In this study, we demonstrate that HIV-specific clonotypes have differing degrees of TemRA differentiation but always maintain a significant proportion of TemRO-phenotype cells. These data indicate that structural constraints of the TCR/peptide major histocompatibility complex interaction play a central role in the TemRA differentiation of HIV-specific CD8+ T cells in chronic HIV-1 infection. Clonotypes with a predominantly TemRA phenotype had a substantial fraction of cells without expression of CD57; and in contrast to the high clonotypic variability of TemRA differentiation, expression of CD57 was highly correlated among T-cell clonotypes within epitope-specific responses, indicating TCR-independent expression of CD57 in vivo. Our data highlight the importance of the structural composition of the TCR repertoire for the effector-memory differentiation of the immune response in chronic viral infections and suggest that TCR-dependent and -independent homeostasis shapes the pathogen-specific effector-memory repertoire in vivo.

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