scholarly journals Peripheral T lymphocyte depletion by apoptosis after CD4 ligation in vivo: selective loss of CD44− and ‘activating’ memory T cells

2008 ◽  
Vol 95 (1) ◽  
pp. 195-200 ◽  
Author(s):  
S. E. M. HOWIE ◽  
A. J. SOMMERFIELD ◽  
E. GRAY ◽  
D. J. HARRISON
Keyword(s):  
T Cells ◽  
T Lymphocyte ◽  
Memory T Cells ◽  
Lymphocyte Depletion ◽  
Selective Loss

IL-7 Differentially Regulates Cell Cycle Entry and Exit of Naive and Memory CD4+ T Lymphocytes: Effects on HIV-Mediated Infection.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2388-2388
Author(s):  
E.L.S. Verhoeyen ◽  
Louise Swainson ◽  
Francois-Loic Cosset ◽  
Naomi Taylor
Keyword(s):  
Cell Cycle ◽  
T Cells ◽  
T Cell ◽  
T Lymphocyte ◽  
Memory T Cells ◽  
T Cell Differentiation ◽  
Cell Cycle Exit ◽  
Cell Cycle Entry ◽  
Hiv 1

Abstract The IL-7 cytokine plays a major role in the in vivo maintenance of polyclonal naive and memory T-cells, positively regulating the survival, differentiation and proliferation of thymocyte and peripheral T lymphocyte populations. Under conditions of lymphopenia due to HIV infection, it has been shown that increased peripheral IL-7 levels correlate with T cell differentiation. Moreover, a short-term exogenous IL-7 treatment enhances T-cell differentiation as well as expansion of naive and memory T-cells. These properties have lead to the proposal that recombinant IL-7 be used as an adjuvant immune therapy in HIV-infected individuals. Nevertheless, primate studies have shown that after an initial increase in in vivo T cell proliferation, there is a substantial drop in the absolute lymphocyte numbers (Fry et al., 2003; Nugeyre et al., 2003). As the bases for this decrease have not yet been elucidated, it is important to assess the long-term biological effects of IL-7 on quiescent human CD4+ T lymphocyte subsets. Here, we demonstrated that although IL-7-stimulated memory T-cells enter into cycle much more rapidly than their naive counterpart (3 days as compared to 6 days), they also exit the cell cycle much earlier, by day 10 vs. day 18. Importantly, cell cycle exit occurred despite the continuous replenishment of IL-7 and was inversely correlated with IL-7 receptor levels. Specifically, IL-7Rα levels were completely downregulated on both naive and memory T subsets within 12 hours post cytokine treatment but were significantly re-upregulated in memory T cell within 8–10 days. In naive lymphocytes, IL7Rα expression was absent during the first 14 days of continuous IL-7 stimulation after which time it slowly increased, with expression coinciding with cell cycle exit. Importantly, the permissivity of IL-7-stimulated CD4+ lymphocytes to infection with an HIV-1 vector was not related to cell cycle entry per se. After extended IL-7 stimulation of the naive T cell subset, they remained more refractory to HIV-1 vector infection than memory cells even though they demonstrated a higher level of cell cycle progression. Moreover, under conditions mimicking the lymph node environment, cell cycle entry was not required for IL-7 mediated infection. The differential effects of recombinant IL-7 on the cell cycle entry-exit status of naive and memory CD4+ T lymphocytes as well as the relative susceptibilities of these CD4+ subsets to HIV-1 vector infection have important implications for the use of this cytokine as an adjuvant immunotherapy.

scholarly journals Lack of Sprouty 1 and 2 enhances survival of effector CD8+ T cells and yields more protective memory cells

2018 ◽  
Vol 115 (38) ◽  
pp. E8939-E8947 ◽  
Author(s):  
Hesham M. Shehata ◽  
Shahzada Khan ◽  
Elise Chen ◽  
Patrick E. Fields ◽  
Richard A. Flavell ◽  
...  
Keyword(s):  
T Cells ◽  
Memory T Cells ◽  
Therapeutic Potential ◽  
Autoimmune Diabetes ◽  
Memory Cells ◽  
Double Knockout ◽  
And Function ◽  
I Cells ◽  
Better Than

Identifying novel pathways that promote robust function and longevity of cytotoxic T cells has promising potential for immunotherapeutic strategies to combat cancer and chronic infections. We show that sprouty 1 and 2 (Spry1/2) molecules regulate the survival and function of memory CD8+ T cells. Spry1/2 double-knockout (DKO) ovalbumin (OVA)-specific CD8+ T cells (OT-I cells) mounted more vigorous autoimmune diabetes than WT OT-I cells when transferred to mice expressing OVA in their pancreatic β-islets. To determine the consequence of Spry1/2 deletion on effector and memory CD8+ T cell development and function, we used systemic infection with lymphocytic choriomeningitis virus (LCMV) Armstrong. Spry1/2 DKO LCMV gp33-specific P14 CD8+ T cells survive contraction better than WT cells and generate significantly more polyfunctional memory T cells. The larger number of Spry1/2 DKO memory T cells displayed enhanced infiltration into infected tissue, demonstrating that absence of Spry1/2 can result in increased recall capacity. Upon adoptive transfer into naive hosts, Spry1/2 DKO memory T cells controlled Listeria monocytogenes infection better than WT cells. The enhanced formation of more functional Spry1/2 DKO memory T cells was associated with significantly reduced mTORC1 activity and glucose uptake. Reduced p-AKT, p-FoxO1/3a, and T-bet expression was also consistent with enhanced survival and memory accrual. Collectively, loss of Spry1/2 enhances the survival of effector CD8+ T cells and results in the formation of more protective memory cells. Deleting Spry1/2 in antigen-specific CD8+ T cells may have therapeutic potential for enhancing the survival and functionality of effector and memory CD8+ T cells in vivo.

scholarly journals A novel humanized mouse model to study the function of human cutaneous memory T cells in vivo in human skin

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Maria M. Klicznik ◽  
Ariane Benedetti ◽  
Laura M. Gail ◽  
Suraj R. Varkhande ◽  
Raimund Holly ◽  
...  
Keyword(s):  
T Cells ◽  
Mouse Model ◽  
Human Skin ◽  
Memory T Cells ◽  
Humanized Mouse ◽  
Humanized Mouse Model

scholarly journals IL-7 and IL-21 are superior to IL-2 and IL-15 in promoting human T cell–mediated rejection of systemic lymphoma in immunodeficient mice

Blood ◽  
2010 ◽  
Vol 115 (17) ◽  
pp. 3508-3519 ◽  
Author(s):  
John C. Markley ◽  
Michel Sadelain
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Transfer ◽  
Memory T Cells ◽  
Tumor Rejection ◽  
Effector Memory ◽  
Transfer Model ◽  
Human T Cell

Abstract The γc-cytokines are critical regulators of immunity and possess both overlapping and distinctive functions. However, comparative studies of their pleiotropic effects on human T cell–mediated tumor rejection are lacking. In a xenogeneic adoptive transfer model, we have compared the therapeutic potency of CD19-specific human primary T cells that constitutively express interleukin-2 (IL-2), IL-7, IL-15, or IL-21. We demonstrate that each cytokine enhanced the eradication of systemic CD19+ B-cell malignancies in nonobese diabetic/severe combined immunodeficient (NOD/SCID)/γcnull mice with markedly different efficacies and through singularly distinct mechanisms. IL-7– and IL-21–transduced T cells were most efficacious in vivo, although their effector functions were not as enhanced as IL-2– and IL-15–transduced T cells. IL-7 best sustained in vitro T-cell accumulation in response to repeated antigenic stimulation, but did not promote long-term T-cell persistence in vivo. Both IL-15 and IL-21 overexpression supported long-term T-cell persistence in treated mice, however, the memory T cells found 100 days after adoptive transfer were phenotypically dissimilar, resembling central memory and effector memory T cells, respectively. These results support the use of γc-cytokines in cancer immunotherapy, and establish that there exists more than 1 human T-cell memory phenotype associated with long-term tumor immunity.

Population doublings of murine CD4+ memory T cells during continuous antigen stimulation in vivo

2014 ◽  
Vol 292 (1-2) ◽  
pp. 45-52 ◽  
Author(s):  
Yoshihiro Kushida ◽  
Jun-ya Ishida ◽  
Masato Fujii ◽  
Maki Touma ◽  
Masamichi Hosono
Keyword(s):  
T Cells ◽  
Memory T Cells ◽  
Antigen Stimulation ◽  
Population Doublings

scholarly journals Antibody to the murine type 3 complement receptor inhibits T lymphocyte-dependent recruitment of myelomonocytic cells in vivo.

1989 ◽  
Vol 169 (2) ◽  
pp. 535-548 ◽  
Author(s):  
H Rosen ◽  
G Milon ◽  
S Gordon
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocyte ◽  
Passive Transfer ◽  
Active Immunization ◽  
Delayed Type Hypersensitivity ◽  
Complement Receptor ◽  
Cell Counts ◽  
Type 3

We have used the delayed-type hypersensitivity (DTH) response to SRBC or tuberculin to examine the role of the murine type 3 complement receptor in T lymphocyte-dependent inflammatory recruitment. Intravenous injection of 5C6, a CR3-specific rat mAb known to impair myelomonocytic adhesion, divided the DTH to SRBC in actively immunized mice into two phases. The early phase, which lasted 24 h, was characterized by maximal oedema and maximal inflammatory recruitment and was 5C6 inhibitable. The later phase was 5C6 resistant and reached a peak 48 h after antigenic challenge and was superimposable on the declining peak seen in control mice. Passive transfer of reactive T cells mixed with antigen was used to examine the myelomonocytic effector arm of the DTH alone. Both passive transfer of cutaneous DTH to SRBC and passive transfer of the largely monocytic T cell-dependent recruitment to tuberculin in the peritoneal cavity were completely abolished by systemic 5C6 treatment. Injection of 5C6-treated donor leukocytes at the site of passive transfer had no effect. Treatment of donor mice with 5C6 at the time of active immunization did not alter their ability to provide reactive T cells for passive transfer. The myelomonocyte-restricted rat mAb 7/4 and the rapidly cleared F(ab')2 fragment of 5C6 showed no inhibition of the DTH. In all cases, inhibition of footpad swelling correlated with histological evidence of inhibition of myelomonocytic cell recruitment. Peritoneal cell counts after local DTH to tuberculin showed complete inhibition of monocyte recruitment. We conclude that CR3 plays a quantitatively important role in T cell-dependent inflammatory recruitment. This is absolute in passive transfer experiments, but only partial after active immunization. Leukocyte CR3 plays a common role in both immunologically specific and nonspecific inflammatory recruitment and provides a target that could possibly be manipulated to therapeutic advantage.

scholarly journals Antigen challenge leads to in vivo activation and elimination of highly polarized TH1 memory T cells

2002 ◽  
Vol 99 (9) ◽  
pp. 6187-6191 ◽  
Author(s):  
N. Hayashi ◽  
D. Liu ◽  
B. Min ◽  
S. Z. Ben-Sasson ◽  
W. E. Paul
Keyword(s):  
T Cells ◽  
Memory T Cells ◽  
Antigen Challenge

Anti-Thymocyte Globulin (ATG) Differentially Depletes naïve and Memory T Cells and Permits Memory-Type Regulatory T Cells

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4670-4670
Author(s):  
Chang-Qing Xia ◽  
Anna Chernatynskaya ◽  
Clive Wasserfall ◽  
Benjamin Looney ◽  
Suigui Wan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Memory T Cells ◽  
Conflicts Of Interest ◽  
T Cell Subsets ◽  
Hematopoietic Stem

Abstract Abstract 4670 Anti-thymocyte globulin (ATG) has been used in clinic for the treatment of allograft rejection and autoimmune diseases. However, its mechanism of action is not fully understood. To our knowledge, how ATG therapy affects naïve and memory T cells has not been well investigated. In this study, we have employed nonobese diabetic mouse model to investigate how administration of anti-thymocyte globulin (ATG) affects memory and naïve T cells as well as CD4+CD25+Foxp3+ regulatory T cells in peripheral blood and lymphoid organs; We also investigate how ATG therapy affects antigen-experienced T cells. Kinetic studies of peripheral blood CD4+ and CD8+ T cells post-ATG therapy shows that both populations decline to their lowest levels at day 3, while CD4+ T cells return to normal levels more rapidly than CD8+ T cells. We find that ATG therapy fails to eliminate antigen-primed T cells, which is consistent with the results that ATG therapy preferentially depletes naïve T cells relative to memory T cells. CD4+ T cell responses post-ATG therapy skew to T helper type 2 (Th2) and IL-10-producing T regulatory type 1 (Tr1) cells. Intriguingly, Foxp3+ regulatory T cells (Tregs) are less sensitive to ATG depletion and remain at higher levels following in vivo recovery compared to controls. Of note, the frequency of Foxp3+ Tregs with memory-like immunophenotype is significantly increased in ATG-treated animals, which might play an important role in controlling effector T cells post ATG therapy. In summary, ATG therapy may modulate antigen-specific immune responses through modulation of naïve and memory T cell pools and more importantly through driving T cell subsets with regulatory activities. This study provides important data for guiding ATG therapy in allogenieic hematopoietic stem cell transplantation and other immune-mediated disorders. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Homeostatic cytokines orchestrate the segregation of CD4 and CD8 memory T-cell reservoirs in mice

Blood ◽  
2011 ◽  
Vol 118 (11) ◽  
pp. 3039-3050 ◽  
Author(s):  
Lili Yang ◽  
Yang Yu ◽  
Manorama Kalwani ◽  
Tai-Wei Joy Tseng ◽  
David Baltimore
Keyword(s):  
T Cells ◽  
Lymph Nodes ◽  
Memory T Cells ◽  
Quantitative Distribution ◽  
Memory T Cell ◽  
Peripheral Lymph ◽  
Cytokine Stimulation ◽  
Homeostatic Cytokines

Abstract Memory T cells (TMs) have been detected in many tissues but their quantitative distribution remains largely undefined. We show that in mice there is a remarkably biased accumulation of long-term CD4 TMs into mucosal sites (mainly gut, especially Peyer patches), and CD8 TMs into lymph nodes and spleen (in particular, peripheral lymph nodes [PLNs]). This distinction correlates with their differentiated expression of PLN- and gut-homing markers. CD8 and CD4 TMs selectively require the expression of PLN-homing marker CCR7 or gut-homing marker α4β7 for maintenance. PLNs and gut supply CD8 and CD4 TMs with their individually favored homeostatic cytokine, IL-15, or IL-7. Cytokine stimulation in turn regulates the different gut-homing marker expression on CD4 and CD8 TMs. IL-15 plays a major role in vivo regulating CD8 TMs homing to PLNs. Thus, the reservoir segregation of CD4 and CD8 TMs meets their individual needs for homeostatic cytokines and is under feedback control of cytokine stimulation.

scholarly journals Protein Kinase B Regulates T Lymphocyte Survival, Nuclear Factor κb Activation, and Bcl-XL Levels in Vivo

2000 ◽  
Vol 191 (10) ◽  
pp. 1721-1734 ◽  
Author(s):  
Russell G. Jones ◽  
Michael Parsons ◽  
Madeleine Bonnard ◽  
Vera S.F. Chan ◽  
Wen-Chen Yeh ◽  
...  
Keyword(s):  
T Cells ◽  
Protein Kinase ◽  
T Lymphocytes ◽  
T Lymphocyte ◽  
Protein Kinase B ◽  
Active Form ◽  
Nuclear Factor ◽  
Clonal Deletion ◽  
Lymphocyte Survival

The serine/threonine kinase protein kinase B (PKB)/Akt mediates cell survival in a variety of systems. We have generated transgenic mice expressing a constitutively active form of PKB (gag-PKB) to examine the effects of PKB activity on T lymphocyte survival. Thymocytes and mature T cells overexpressing gag-PKB displayed increased active PKB, enhanced viability in culture, and resistance to a variety of apoptotic stimuli. PKB activity prolonged the survival of CD4+CD8+ double positive (DP) thymocytes in fetal thymic organ culture, but was unable to prevent antigen-induced clonal deletion of thymocytes expressing the major histocompatibility complex class I–restricted P14 T cell receptor (TCR). In mature T lymphocytes, PKB can be activated in response to TCR stimulation, and peptide-antigen–specific proliferation is enhanced in T cells expressing the gag-PKB transgene. Both thymocytes and T cells overexpressing gag-PKB displayed elevated levels of the antiapoptotic molecule Bcl-XL. In addition, the activation of peripheral T cells led to enhanced nuclear factor (NF)-κB activation via accelerated degradation of the NF-κB inhibitory protein IκBα. Our data highlight a physiological role for PKB in promoting survival of DP thymocytes and mature T cells, and provide evidence for the direct association of three major survival molecules (PKB, Bcl-XL, and NF-κB) in vivo in T lymphocytes.

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