scholarly journals CMV Status Drives Distinct Trajectories of CD4+ T Cell Differentiation

2021 ◽  
Vol 12 ◽  
Author(s):  
Weiwen Zhang ◽  
Anna B. Morris ◽  
Erica V. Peek ◽  
Geeta Karadkhele ◽  
Jennifer M. Robertson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
De Novo ◽  
Memory T Cells ◽  
Gene Set Enrichment Analysis ◽  
Careful Examination ◽  
Effector Memory ◽  
Effector Memory T Cells ◽  
Cytotoxic Function

Cytomegalovirus (CMV) is one of the most commonly recognized opportunistic pathogens and remains the most influential known parameter in shaping an individual’s immune system. As such, T cells induced by CMV infection could have a long-term impact on subsequent immune responses. Accumulating evidence indicates that memory T cells developed during past bacterial and viral infection can cross-react with unrelated pathogens, including transplant antigens, and can alter responses to de novo infections, vaccines, cancers, or rejection. Therefore, careful examination of T cell responses elicited by CMV is warranted to understand their potentially beneficial or harmful roles in future major immune events. Our detailed exploration of the distribution, phenotype, TCR repertoire and transcriptome of CD4+ T cells within CMV seropositive healthy individuals using high-dimensional flow cytometry and single cell multi-omics sequencing reveals that CMV seropositivity has highly significant age-independent effects, leading to a reduction in CD4+ naïve T cells and an expansion of CD4+ effector memory T cells and CD45RA+ effector memory T cells. These induced CD4+ effector memory T cells undergo a specific differentiation trajectory resulting in a subpopulation of CD57+CD27-CD28-CD244+ CD4+ T cells with cytotoxic function and TCR oligoclonality for optimal controlled coexistence with cytomegalovirus. Through gene set enrichment analysis, we found that this subpopulation is similar to virus-specific CD8+ T cells and T cells that mediate acute rejection in patients using tacrolimus and belatacept, a selective costimulation blocker. Together, these data suggest that memory CD4+ T cells induced by cytomegalovirus are formed via a distinct differentiation program to acquire cytotoxic function and can be potentially detrimental to transplant patients adopting costimulation blockade immunosuppressive regimen.

scholarly journals Aging Of Antiviral CD8+ Memory T Cells Fosters Increased Survival, Metabolic Adaptations And Lymphoid Tissue Homing

2017 ◽  
Author(s):  
Bennett Davenport ◽  
Jens Eberlein ◽  
Verena van der Heide ◽  
Kevin Jhun ◽  
Tom T. Nguyen ◽  
...  
Keyword(s):  
T Cells ◽  
Fatty Acid ◽  
T Cell ◽  
Memory T Cells ◽  
Gene Set Enrichment Analysis ◽  
Enrichment Score ◽  
Effector Memory ◽  
White Pulp ◽  
Effector Memory T Cells ◽  
Metabolic Adaptations

ABSTRACTAging of established antiviral T cell memory fosters a series of progressive adaptations that paradoxically improve rather than compromise protective CD8+T cell immunity. We now provide evidence that this gradual evolution, the pace of which is contingent on the precise context of the primary response, also impinges on the molecular mechanisms that regulate CD8+ memory T cell (CD8+TM) homeostasis. Over time, CD8+TM become more resistant to apoptosis and acquire enhanced cytokine responsiveness without adjusting their homeostatic proliferation rates; concurrent metabolic adaptations promote increased CD8+TM quiescence and fitness but also impart the re-acquisition of a partial effector-like metabolic profile; and a gradual redistribution of aging CD8+TM from blood and nonlymphoid tissues to lymphatic organs results in CD8+TM accumulations in bone marrow, splenic white pulp and particularly lymph nodes. Altogether, these data demonstrate how temporal alterations of fundamental homeostatic determinants converge to render aged CD8+TM poised for greater recall responses.ABBREVIATIONSATadoptive transferATGLadipose triglyceride lipaseBMPblood and marginated poolFA, FAO, FAS, FASNfatty acid, fatty acid oxidation, fatty acid synthesis, fatty acid synthaseFSC, SSCforward scatter, side scatterGMFIgeometric mean of fluorescence intensityGP, NPglycoprotein, nucleoproteinGSEAgene set enrichment analysisGSHglutathioneIo, IIoprimary, secondaryKEGGKyoto Encyclopedia of Genes and GenomesLALlysosomal acid lipase (LIPA)LCMVlymphocytic choriomeningitis virusNESnormalized enrichment scoreNLTsnonlymphoid tissuesO, Yold, youngOxPhosoxidative phosphorylationp14 cellsTCRtg CD8+T cells specific for the LCMV-GP33-41 determinantRP, WPred pulp, white pulp (spleen)T cell subsetsTEeffector T cellsTCMcentral memory T cells (CD62Lhi)TEMeffector memory T cells (CD62Llo)TEMRAterminally differentiated CD45RA+ effector memory T cells (human)TMmemory T cellsTMPmemory-phenotype T cells (CD44hi)TNnaïve T cells (CD44lo)TRMresident memory T cells (CD69/CD103-enriched)TCRtgT cell receptor transgenicTSLPThymic stromal lymphopoietin

Flt3 ligand augmentation of T cell mitogenesis and expansion of type 1 effector/memory T cells

2002 ◽  
Vol 2 (7) ◽  
pp. 925-940 ◽  
Author(s):  
R Lee Mosley ◽  
Prahlad Parajuli ◽  
Vladimir Pisarev ◽  
Jennifer Chavez ◽  
Amy Meeks ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Memory T Cells ◽  
Effector Memory ◽  
Flt3 Ligand ◽  
Effector Memory T Cells

Ex Vivo Fludarabine Selectively Depletes Human Naive T-Cell Subsets: A Step Toward Modifying Donor Lymphocyte Infusion.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1071-1071
Author(s):  
Melody M. Smith ◽  
Cynthia R. Giver ◽  
Edmund K. Waller ◽  
Christopher R. Flowers
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Ex Vivo ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Naïve T Cell ◽  
Naive T Cell

Abstract Ex vivo modification of donor lymphocytes with purine analogs (mDL) may help to minimize graft versus host disease (GvHD) while providing beneficial graft versus leukemia (GvL) effects. In a murine model system, we have shown that allogeneic donor splenocytes, treated with fludarabine ex vivo have significantly reduced GvHD activity when transferred to irradiated recipient mice, and retain anti-viral and GvL activities (Giver, 2003). This effect appears to be mediated by relative depletion of donor CD4 CD44low, “naive” T-cells. As a first step toward developing mDL for use in patients, we sought to evaluate the effects of ex vivo fludarabine exposure on human T-cell subsets, and to determine the minimum dose of fludarabine required to achieve this effect. Methods: Peripheral blood mononuclear cell samples from 6 healthy volunteers were evaluated at 0, 24, 48, and 72 hour time points after ex vivo incubation in varying dosages of fludarabine: 2, 5, and 10(n=3) mcg/ml. Fludarabine incubated samples were compared to samples that received no fludarabine (untreated). The total viable cell number was determined and the fractions and absolute numbers of viable CD4 and CD8 naïve and memory T-cells were determined using flow cytometry after incubation with 7-AAD (dead cell stain), CD4, CD8, CD45RA, CD62L, and CCR7 antibodies, and measuring the total viable cells/ml. Results: The numbers of viable CD4 and CD8 T-cells remained relatively stable in control cultures. Without fludarabine, the average viability at 72 hr of naive and memory T-cells were 92% and 77% for CD4 and 86% and 63% for CD 8 (Fig. 1A). Naive CD4 T-cells were more sensitive to fludarabine-induced death than memory CD4 cells. At 72 hr, the average viability of fludarabine-treated naive CD4 T-cells was 33% at 2 mcg/ml (8.2X the reduction observed in untreated cells) and 30% at 5 mcg/ml, while memory CD4 T-cells averaged 47% viability at 2 mcg/ml (2.3X the reduction observed in untreated cells) (Fig. 1B) and 38% at 5 mcg/ml. The average viability of naive CD8 T-cells at 72 hr was 27% at 2 mcg/ml and 20% at 5 mcg/ml, while memory CD8 T-cell viability was 22% at 2 mcg/ml and 17% at 5 mcg/ml. Analyses on central memory, effector memory, and Temra T-cells, and B-cell and dendritic cell subsets are ongoing. The 5 and 10 mcg/ml doses also yielded similar results in 3 initial subjects, suggesting that 2 mcg/ml or a lower dose of fludarabine is sufficient to achieve relative depletion of the naive T-cell subset. Conclusions: Future work will determine the minimal dose of fludarabine to achieve this effect, test the feasibility of using ex vivo nucleoside analog incubation to reduce alloreactivity in samples from patient/donor pairs, and determine the maximum tolerated dose of mDL in a phase 1 clinical trial with patients at high risk for relapse and infectious complications following allogeneic transplantation. Figure Figure

scholarly journals CD8+CD44hi but not CD4+CD44hi memory T cells mediate potent graft antilymphoma activity without GVHD

Blood ◽  
2011 ◽  
Vol 117 (11) ◽  
pp. 3230-3239 ◽  
Author(s):  
Suparna Dutt ◽  
Jeanette Baker ◽  
Holbrook E. Kohrt ◽  
Neeraja Kambham ◽  
Mrinmoy Sanyal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Memory T Cells ◽  
Cell Subset ◽  
B Cell Lymphoma ◽  
Effector Memory ◽  
T Cell Subset ◽  
Progressive Growth

Abstract Allogeneic hematopoietic cell transplantation can be curative in patients with leukemia and lymphoma. However, progressive growth of malignant cells, relapse after transplantation, and graft-versus-host disease (GVHD) remain important problems. The goal of the current murine study was to select a freshly isolated donor T-cell subset for infusion that separates antilymphoma activity from GVHD, and to determine whether the selected subset could effectively prevent or treat progressive growth of a naturally occurring B-cell lymphoma (BCL1) without GVHD after recipients were given T cell–depleted bone marrow transplantations from major histocompatibility complex–mismatched donors. Lethal GVHD was observed when total T cells, naive CD4+ T cells, or naive CD8+ T cells were used. Memory CD4+CD44hi and CD8+CD44hi T cells containing both central and effector memory cells did not induce lethal GVHD, but only memory CD8+ T cells had potent antilymphoma activity and promoted complete chimerism. Infusion of CD8+ memory T cells after transplantation was able to eradicate the BCL1 lymphoma even after progressive growth without inducing severe GVHD. In conclusion, the memory CD8+ T-cell subset separated graft antilymphoma activity from GVHD more effectively than naive T cells, memory CD4+ T cells, or memory total T cells.

Tolerogenic dendritic cells inhibit antiphospholipid syndrome derived effector/memory CD4+ T cell response to β2GPI

2011 ◽  
Vol 71 (1) ◽  
pp. 120-128 ◽  
Author(s):  
Honorio Torres-Aguilar ◽  
Miri Blank ◽  
Shaye Kivity ◽  
Mudi Misgav ◽  
Jacob Luboshitz ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Proliferative Response ◽  
Memory T Cells ◽  
Tolerance Induction ◽  
Effector Memory ◽  
Effector Memory T Cells ◽  
Tolerogenic Dendritic Cells ◽  
Specific Tolerance

ObjectivesThe importance of β2-glycoprotein I (β2GPI)-specific CD4+ T cells in the development of pathogenic processes in patients with antiphospholipid syndrome (APS) and APS mouse models is well established. Therefore, our objective is to manipulate the β2GPI specific CD4+ T cells using tolerogenic dendritic cells (tDCs) to induce tolerance. We aim to evaluate the capability of tDCs to induce antigen-specific tolerance in effector/memory T cells from patients with APS and to elucidate the involved mechanism.MethodsDCs and tDCs were produced from patients with APS peripheral-blood-monocytes, using specific cytokines. β2GPI-specific tolerance induction was investigated by coculturing control DC (cDC) or tDC, β2GPI-loaded, with autologous effector/memory T cells, evaluating the proliferative response, phenotype, cytokines secretion, viability and regulatory T cells.ResultsHuman monocyte-derived DCs treated with interleukin (IL)-10 and transforming growth factor β-1 (10/TGF-DC) induced β2GPI-specific-unresponsiveness in effector/memory CD4+ T cells (46.5%±26.0 less proliferation) in 16 of 20 analysed patients with APS, without affecting the proliferative response to an unrelated candidin. In five analysed patients, 10/TGF-DC-stimulated T cells acquired an IL-2lowinterferon γlowIL-10high cytokine profile, with just a propensity to express higher numbers of Foxp3+CTLA-4+ cells, but with an evident suppressive ability. In four of 10 analysed patients, 10/TGF-DC-stimulated T cell hyporesponsiveness could not be reverted and showed higher percentages of late apoptosis, p<0.02.ConclusionsThe inherent tolerance induction resistance of activated T cells present during the development of autoimmune diseases has delayed the application of tDC as an alternative therapy. This study highlights the 10/TGF-DC feasibility to induce antigen-specific unresponsiveness in autoreactive T cells generated in patients with APS by inducing apoptosis or T cells with regulatory abilities.

Unique gene expression program of human germinal center T helper cells

Blood ◽  
2004 ◽  
Vol 104 (7) ◽  
pp. 1952-1960 ◽  
Author(s):  
Chang H. Kim ◽  
Hyung W. Lim ◽  
Jong R. Kim ◽  
Lusijah Rott ◽  
Peter Hillsamer ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Germinal Center ◽  
Memory T Cells ◽  
Effector Memory ◽  
T Helper ◽  
Th Cells ◽  
Effector Memory T Cells ◽  
Expression Program

Abstract Gene expression profiling was used to compare the gene expression patterns of human germinal center (GC) T helper (Th) cells with other CD4+ T-cell subsets (naive, central, and effector memory T cells). GC-Th cells, specifically localized in germinal centers to help B cells, are distantly related to central and effector memory T cells in global gene expression profiles. GC-Th cells displayed substantial differences in mRNA for adhesion molecules, chemoattractant receptors, and cytokines compared with other populations. Distinct expression of transcriptional factors by GC-Th cells is consistent with the hypothesis that they may be different from other T cells in cell lineage. Interestingly, CXCL13, a critical chemokine for B-cell entry to lymphoid follicles, is one of the most highly up-regulated genes in GC-Th cells. GC-Th cells (but not other T cells) produce and secrete large amounts of functional CXCL13 upon T-cell receptor activation, a process that is dependent on costimulation, requires translation and transcription, and is dramatically enhanced by activation in the presence of GC-B cells. This study revealed for the first time the unique gene expression program of GC-Th cells.

scholarly journals Circulating HLA-DR+CD4+ effector memory T cells resistant to CCR5 and PD-L1 mediated suppression compromise regulatory T cell function in tuberculosis

2018 ◽  
Vol 14 (9) ◽  
pp. e1007289 ◽  
Author(s):  
Asma Ahmed ◽  
Vasista Adiga ◽  
Soumya Nayak ◽  
J. Anto Jesuraj Uday Kumar ◽  
Chirag Dhar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cell ◽  
Cell Function ◽  
Memory T Cells ◽  
Effector Memory ◽  
Effector Memory T Cells ◽  
T Cell Function ◽  
Hla Dr
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