CRTAM determines the CD4+ cytotoxic T lymphocyte lineage

Naive T cells differentiate into various effector T cells, including CD4+ helper T cell subsets and CD8+ cytotoxic T cells (CTL). Although cytotoxic CD4+ T cells (CD4+CTL) also develop from naive T cells, the mechanism of development is elusive. We found that a small fraction of CD4+ T cells that express class I–restricted T cell–associated molecule (CRTAM) upon activation possesses the characteristics of both CD4+ and CD8+ T cells. CRTAM+ CD4+ T cells secrete IFN-γ, express CTL-related genes, such as eomesodermin (Eomes), Granzyme B, and perforin, after cultivation, and exhibit cytotoxic function, suggesting that CRTAM+ T cells are the precursor of CD4+CTL. Indeed, ectopic expression of CRTAM in T cells induced the production of IFN-γ, expression of CTL-related genes, and cytotoxic activity. The induction of CD4+CTL and IFN-γ production requires CRTAM-mediated intracellular signaling. CRTAM+ T cells traffic to mucosal tissues and inflammatory sites and developed into CD4+CTL, which are involved in mediating protection against infection as well as inducing inflammatory response, depending on the circumstances, through IFN-γ secretion and cytotoxic activity. These results reveal that CRTAM is critical to instruct the differentiation of CD4+CTL through the induction of Eomes and CTL-related gene.

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Critical role of CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution

Blood ◽

10.1182/blood-2012-03-418624 ◽

2012 ◽

Vol 120 (9) ◽

pp. 1856-1867 ◽

Cited By ~ 49

Author(s):

Ming Zeng ◽

Mirko Paiardini ◽

Jessica C. Engram ◽

Greg J. Beilman ◽

Jeffrey G. Chipman ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Antiretroviral Therapy ◽

Cd4 T Cells ◽

Lymphoid Tissue ◽

T Cell Subsets ◽

Tissue Structure ◽

Naive T Cells ◽

Naïve T Cells ◽

Hiv 1

Abstract Loss of the fibroblastic reticular cell (FRC) network in lymphoid tissues during HIV-1 infection has been shown to impair the survival of naive T cells and limit immune reconstitution after antiretroviral therapy. What causes this FRC loss is unknown. Because FRC loss correlates with loss of both naive CD4 and CD8 T-cell subsets and decreased lymphotoxin-β, a key factor for maintenance of FRC network, we hypothesized that loss of naive T cells is responsible for loss of the FRC network. To test this hypothesis, we assessed the consequences of antibody-mediated depletion of CD4 and CD8 T cells in rhesus macaques and sooty mangabeys. We found that only CD4 T-cell depletion resulted in FRC loss in both species and that this loss was caused by decreased lymphotoxin-β mainly produced by the CD4 T cells. We further found the same dependence of the FRC network on CD4 T cells in HIV-1–infected patients before and after antiretroviral therapy and in other immunodeficiency conditions, such as CD4 depletion in cancer patients induced by chemotherapy and irradiation. CD4 T cells thus play a central role in the maintenance of lymphoid tissue structure necessary for their own homeostasis and reconstitution.

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Life after the thymus: CD31+ and CD31− human naive CD4+ T-cell subsets

Blood ◽

10.1182/blood-2008-02-139154 ◽

2009 ◽

Vol 113 (4) ◽

pp. 769-774 ◽

Cited By ~ 198

Author(s):

Siegfried Kohler ◽

Andreas Thiel

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

T Cell Subsets ◽

Naive T Cells ◽

Naïve T Cells ◽

Cell Pool ◽

The Impact ◽

Naïve T Cell ◽

Naive T Cell

Abstract Early in life, thymic export establishes the size and the diversity of the human naive T-cell pool. Yet, on puberty thymic activity drastically decreases. Because the overall size of the naive T-cell pool decreases only marginally during ageing, peripheral postthymic expansion of naive T cells has been postulated to account partly for the maintenance of T-cell immunity in adults. So far, the analysis of these processes had been hampered by the inability to distinguish recent thymic emigrants from proliferated, peripheral, naive T cells. However, recently, CD31 has been introduced as a marker to distinguish 2 subsets of naive CD4+ T cells with distinct T-cell receptor excision circle (TREC) content in the peripheral blood of healthy humans. Here, we review studies that have characterized TREChi CD31+ thymicnaive CD4+ T cells and have accordingly used the assessment of this distinct subset of naive CD4+ T cells as a correlate of thymic activity. We will discuss further potential clinical applications and how more research on CD31+ thymicnaive and CD31− centralnaive CD4+ T cells may foster our knowledge of the impact of thymic involution on immune competence.

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Long-Term Depletion of Naive T Cells in Patients Treated for Hodgkin's Disease

Blood ◽

10.1182/blood.v90.9.3662 ◽

1997 ◽

Vol 90 (9) ◽

pp. 3662-3672 ◽

Cited By ~ 49

Author(s):

Nobukazu Watanabe ◽

Stephen C. De Rosa ◽

Anthony Cmelak ◽

Richard Hoppe ◽

Leonore A. Herzenberg ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Hodgkin's Disease ◽

Hodgkin’S Disease ◽

Cell Subset ◽

T Cell Subsets ◽

Naive T Cells ◽

Naïve T Cells ◽

Cell Counts

Abstract We investigated the representation of T cells in patients who had been treated for Hodgkin's disease (HD). We found a marked depletion in both CD4 and CD8 naive T-cell counts that persists up to 30 years after completion of treatment. In contrast, CD4 and CD8 memory T-cell subsets recovered to normal or above normal levels by 5 years posttreatment. Thus, the previously-reported long-term deficit in total CD4 T-cell counts after treatment for HD is due to specific depletion of naive T cells. Similarly, total CD8 T-cell counts return to normal by 5 years only because CD8 memory T cells expand to higher than normal levels. These findings suggest that the treatment (mediastinal irradiation) results in a longterm dysregulation of T-cell subset homeostasis. The profound depletion of naive T cells may explain the altered T-cell function in treated patients, including the poor response to immunization after treatment for HD. Further, in some individuals, we identified expansions of unusual subsets expressing low levels of CD8. Eight-color fluorescence-activated cell sorting analyses showed that these cells largely express CD8αα homodimers and CD57, consistent with the phenotype of potentially extrathymically derived T cells. In addition, these cells, both CD4+ and CD4−, are probably cytotoxic lymphocytes, as they express high levels of intracellular perforin. In adults treated for HD, an increased activity of extrathymic T-cell differentiation may partially compensate for the loss of thymic-derived T cells.

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Response of naive antigen-specific CD4+ T cells in vitro: characteristics and antigen-presenting cell requirements.

Journal of Experimental Medicine ◽

10.1084/jem.176.5.1431 ◽

1992 ◽

Vol 176 (5) ◽

pp. 1431-1437 ◽

Cited By ~ 156

Author(s):

M Croft ◽

D D Duncan ◽

S L Swain

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cd4 Cells ◽

Peptide Antigen ◽

Naive T Cells ◽

Naïve T Cells ◽

Antigen Presenting

Because of the low frequency of T cells for any particular soluble protein antigen in unprimed animals, the requirements for naive T cell responses in specific antigens have not been clearly delineated and they have been difficult to study in vitro. We have taken advantage of mice transgenic for the V beta 3/V alpha 11 T cell receptor (TCR), which can recognize a peptide of cytochrome c presented by IEk. 85-90% of CD4+ T cells in these mice express the transgenic TCR, and we show that almost all such V beta 3/V alpha 11 receptor-positive cells have a phenotype characteristic of naive T cells, including expression of high levels of CD45RB, high levels of L-selectin (Mel-14), low levels of CD44 (Pgp-1), and secretion of interleukin 2 (IL-2) as the major cytokine. Naive T cells, separated on the basis of CD45RB high expression, gave vigorous responses (proliferation and IL-2 secretion) to peptide antigen presented in vitro by a mixed antigen-presenting cell population. At least 50% of the T cell population appeared to respond, as assessed by blast transformation, entry into G1, and expression of increased levels of CD44 by 24 h. Significant contributions to the response by contaminating memory CD4+ cells were ruled out by demonstrating that the majority of the CD45RB low, L-selectin low, CD44 high cells did not express the V beta 3/V alpha 11 TCR and responded poorly to antigen. We find that proliferation and IL-2 secretion of the naive CD4 cells is minimal when resting B cells present peptide antigen, and that both splenic and bone marrow-derived macrophages are weak stimulators. Naive T cells did respond well to high numbers of activated B cells. However, dendritic cells were the most potent stimulators of proliferation and IL-2 secretion at low cell numbers, and were far superior inducers of IL-2 at higher numbers. These studies establish that naive CD4 T cells can respond vigorously to soluble antigen and indicate that maximal stimulation can be achieved by presentation of antigen on dendritic cells. This model should prove very useful in further investigations of activation requirements and functional characteristics of naive helper T cells.

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Abstract 424: Effector T Cells Induce Cardiac Fibroblasts Transition to Myofibroblasts & Contribute to Pressure Overload Induced Cardiac Fibrosis

Circulation Research ◽

10.1161/res.119.suppl_1.424 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Tania A Nevers ◽

Ane Salvador ◽

Francisco Velazquez ◽

Mark Aronovitz ◽

Robert Blanton

Keyword(s):

T Cells ◽

T Cell ◽

Cardiac Fibrosis ◽

Cardiac Fibroblasts ◽

Pressure Overload ◽

Effector T Cells ◽

T Cell Subsets ◽

Naive T Cells ◽

Effector T Cell ◽

Naïve T Cells

Background: Cardiac fibrogenesis is a major pathogenic factor that occurs in heart failure (HF) and results in contractile dysfunction and ventricular dilation. Recently, we showed that T cell deficient mice (TCRα -/- ) do not develop cardiac fibrosis (CF) and have preserved cardiac function in the thoracic aortic constriction (TAC) mouse model of pressure overload (PO). Specifically, CD4 + T cells are activated in the cardiac draining lymph nodes and infiltrate the LV, where the Th1 and Th17 effector T cell signature transcription factors are significantly upregulated as compared with control mice. However, the T cell subsets involved and the mechanisms by which they contribute to CF and pathogenesis of non-ischemic HF remains to be determined. Thus, we hypothesize that heart infiltrated effector T cells perpetuate the fibrotic response by regulating the differentiation and activation of extracellular matrix-producing cardiac myofibroblasts. Methods and Results: Naïve or effector T cells differentiated in vitro or isolated from mice undergoing TAC or Sham surgery were co-cultured with adult C57BL/6 cardiac fibroblasts (CFB). In contrast with naïve T cells, effector T cells and PO activated T cells strongly adhered to CFB and mediated fibroblast to myofibroblasts transition as depicted by immunofluorescence expression of SMAα. Effector T cell supernatants only slightly mediated this transition, indicating that effector T cells direct contact with CFB, rather than cytokine release is required to mediate CFB transformation. Adoptive transfer of effector, but not naïve T cells, into TCRα -/- recipient mice in the onset of TAC resulted in T cells infiltration into the left ventricle and increased CF. Conclusions: Our data indicate that CD4+ effector T cells directly interact with CFB to induce CF in response to PO induced CF. Future studies will determine the adhesion mechanisms regulating this crosstalk and evaluate the pro-fibrotic mechanisms induced and whether this is a T effector cell specific subset. These results will provide an attractive tool to counteract the inflammatory/fibrotic process as an alternative option for the treatment of CF in non- ischemic HF.

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In vitro responses of human CD45R0brightRA− and CD45R0−RAbright T cell subsets and their relationship to memory and naive T cells

European Journal of Immunology ◽

10.1002/eji.1830270937 ◽

1997 ◽

Vol 27 (9) ◽

pp. 2383-2390 ◽

Cited By ~ 72

Author(s):

Joyce L. Young ◽

Judith M. Ramage ◽

J. S. Hill Gaston ◽

Peter C. L. Beverley

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Subsets ◽

Naive T Cells ◽

Naïve T Cells

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Donor Lymphocyte Infusions Correct Deficiency of Naive T Cells and Improve T-Cell Competence after Allogeneic Haematopoietic Stem Cell Transplantation with Lymphocyte Depletion

Blood ◽

10.1182/blood.v128.22.2233.2233 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2233-2233

Author(s):

Monera Al Rukhayes ◽

Victoria T Potter ◽

Pilar Perez-Abellan ◽

Jesus Feliu ◽

Lajos Floro ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Healthy Volunteers ◽

Cd8 T Cells ◽

Cd4 T Cells ◽

Haematopoietic Stem Cell ◽

Naive T Cells ◽

Lymphocyte Depletion ◽

Naïve T Cells ◽

Repertoire Diversity

Abstract Lymphocyte-depletion effectively reduces risk of graft versus host disease (GvHD) after allogeneic haematopoietic stem cell transplantation (allo-HSCT), but risk of infections and malignant disease relapse remains high. We have previously reported that pre-emptive donor lymphocyte infusions (pDLI) given to patients after allo-HSCT for myeloid malignancies to reverse falling donor T-cell chimerism improve overall and relapse-free survival. GvHD rates after pDLI were not high and grade rarely severe. To investigate the basis for better outcome after pDLI, we have assessed recovery of lymphocyte subsets, T-cell receptor (TCR) diversity and T-cell functional competence after allo-HSCT with fludarabine and busulphan in cohorts of 59 patients (median age 59) given alemtuzumab for lymphocyte-depletion and 34 patients (median age 58) given anti-thymocyte globulin (ATG). Lymphocytes were significantly less depleted with ATG compared to alemtuzumab (Day 30: Median 3.9 x 108/liter versus 2.3x108/liter, P=0.03) but numbers for both ATG and alemtuzumab remained significantly below the normal range (median 2.34x109/liter for 11 aged-matched healthy volunteers) for at least one year (Day 360 P<0.005: Median 8.35 x 108/liter after ATG; median 1.04 x 109/liter after alemtuzumab). Lymphocyte subset composition was similar after ATG or alemtuzumab, and abnormal. Notable, the T-cell population comprised only memory and effector T cells early after HSCT. These cells expressed significantly higher levels of Ki67 than T cells from healthy volunteers (Day 30 P<0.005: Median CD4 T cells 41.3% Ki67+ after ATG, 66% after alemtuzumab compared to 2.51% for healthy volunteers; median CD8 T cells 18.5% Ki67+ after ATG, 50.8% after alemtuzumab compared to 2.58% for healthy volunteers). This marker is indicative of homeostatic proliferation likely driven by increased levels of IL7 and IL15 detected in the serum of patients early after HSCT compared to healthy volunteers (Day 30 P=0.066 and P<0.005 respectively). Higher frequency of T cells expressing the proliferation marker in patients treated with alemtuzumab was associated with high frequencies of T cells expressing the PD1 marker, indicative of exhaustion (Day 30 P<0.005: Median CD4 T cells 84.0% PD1+ after alemtuzumab compared to 6.35% for healthy volunteers; median CD8 T cells 49.1% PD1+ after alemtuzumab compared to 12.3% for healthy volunteers). Expression of PD1 by T cells was near normal in patients treated with ATG. Naïve T cells were typically absent for at least six months after HSCT following lymphocyte depletion with ATG or alemtuzumab, and any subsequent recovery was poor. In contrast, the naïve T-cell population increased rapidly in patients after pDLI (n=18). Six of these patients received pDLI early after HSCT (at 3-5 months) and naïve T-cell recovery was significantly enhanced at six months compared to patients that did not receive pDLI (Day 180 P<0.005: Median 19.25% naïve CD4 T cells compared to 1.36%; median 23.5% naïve CD8 T cells compared to 3.48%). Naïve T cells are the main source of repertoire diversity and responsible for responses to antigens not previously encountered. Analysis of the TCR β chain repertoire of five patients by deep sequencing revealed that pDLI boosts repertoire diversity. For example, unique TCR β chain sequences increased 31-fold in 150 days after pDLI compared to a 2-fold increase during a similar period for another patient that did not receive DLI. Furthermore, instances of emergence of public clonotypes specific for CMV or EBV that were not detected before DLI were seen in virus-positive patients whose donors were virus-negative. Emergence and rapid expansion of donor-derived clonotypes to frequencies up to 6.75% suggests that naïve T cells present in the DLI had been primed upon encounter with virus in the patient. In vitro stimulation with overlapping 15-mer peptide libraries for CMV antigens and EBV antigens followed by assessment of activation marker expression and interferon-γ, MIP-1β, and TNF-α production showed that virus-specific T-cell responses increased in magnitude and poly-functionality after DLI. These findings show that DLI replenishes naïve T cells and restores ability to respond to viral antigens previously unseen. By inference, this may extend to leukaemia antigens and underlie the reduced rate of malignant disease relapse seen in patients given pDLI. Disclosures No relevant conflicts of interest to declare.

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Dysregulated lymphocyte proliferation and differentiation in patients with rheumatoid arthritis

Blood ◽

10.1182/blood-2002-03-0671 ◽

2002 ◽

Vol 100 (13) ◽

pp. 4550-4556 ◽

Cited By ~ 102

Author(s):

Frederique Ponchel ◽

Ann W. Morgan ◽

Sarah J. Bingham ◽

Mark Quinn ◽

Maya Buch ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Cell Differentiation ◽

T Cell ◽

Large Population ◽

Chronic Inflammatory Disease ◽

T Cell Differentiation ◽

T Cell Subsets ◽

Naive T Cells ◽

Naïve T Cells

Rheumatoid arthritis (RA) is a chronic, inflammatory disease of the synovium of uncertain pathogenesis. A number of phenotypic and functional T-cell defects have been described in RA, including abnormal clonal expansions and suppressed proliferative responses, which suggest a defect in T-cell differentiation. Here, we show that RA patients possess fewer naive CD4+ T cells than healthy controls. Furthermore, a smaller proportion of these cells contains a T-cell receptor excision circle (TREC). Patients with RA also have unusual populations of T cells. These include immature cells characterized as CD45RBbrightCD45RA+CD62L− by flow cytometry and a large population that coexpresses CD45RA and CD45RO. These cells are hyperresponsive to mitogen and TCR stimulation when compared to naive cells. Additionally, an unusual putative central memory subset expressing CD62L, but not CD45RA, appears in RA patients at the expense of more typical cells. Levels of C-reactive protein correlate inversely with the TREC content of naive T cells and positively with the sizes of naive and immature atypical T-cell subsets. These data suggest that inflammation drives proliferation of naive T cells in RA and encourages their differentiation into atypical, hyperresponsive progeny. TREC content of individual naive and atypical T-cell subsets suggests an ontogeny consistent with this hypothesis. These studies provide further evidence of a T-cell differentiation defect in RA, which could explain some of the well-characterized immunologic features of the disease.

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Cortisol and epinephrine control opposing circadian rhythms in T cell subsets

Blood ◽

10.1182/blood-2008-11-190769 ◽

2009 ◽

Vol 113 (21) ◽

pp. 5134-5143 ◽

Cited By ~ 172

Author(s):

Stoyan Dimitrov ◽

Christian Benedict ◽

Dennis Heutling ◽

Jürgen Westermann ◽

Jan Born ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Circadian Rhythms ◽

Cd8 T Cells ◽

Low Dose ◽

Cd8 T Cell ◽

T Cell Subsets ◽

Naive T Cells ◽

Naïve T Cells ◽

Cell Counts

Abstract Pronounced circadian rhythms in numbers of circulating T cells reflect a systemic control of adaptive immunity whose mechanisms are obscure. Here, we show that circadian variations in T cell subpopulations in human blood are differentially regulated via release of cortisol and catecholamines. Within the CD4+ and CD8+ T cell subsets, naive cells show pronounced circadian rhythms with a daytime nadir, whereas (terminally differentiated) effector CD8+ T cell counts peak during daytime. Naive T cells were negatively correlated with cortisol rhythms, decreased after low-dose cortisol infusion, and showed highest expression of CXCR4, which was up-regulated by cortisol. Effector CD8+ T cells were positively correlated with epinephrine rhythms, increased after low-dose epinephrine infusion, and showed highest expression of β-adrenergic and fractalkine receptors (CX3CR1). Daytime increases in cortisol via CXCR4 probably act to redistribute naive T cells to bone marrow, whereas daytime increases in catecholamines via β-adrenoceptors and, possibly, a suppression of fractalkine signaling promote mobilization of effector CD8+ T cells from the marginal pool. Thus, activation of the major stress hormones during daytime favor immediate effector defense but diminish capabilities for initiating adaptive immune responses.

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One naive T cell, multiple fates in CD8+ T cell differentiation

Journal of Experimental Medicine ◽

10.1084/jem.20091175 ◽

2010 ◽

Vol 207 (6) ◽

pp. 1235-1246 ◽

Cited By ~ 112

Author(s):

Carmen Gerlach ◽

Jeroen W.J. van Heijst ◽

Erwin Swart ◽

Daoud Sie ◽

Nicola Armstrong ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Large Scale ◽

Cd8 T Cell ◽

T Cell Subsets ◽

High Avidity ◽

Naive T Cells ◽

Memory T Cell ◽

Naïve T Cells ◽

Large Scale Assessment

The mechanism by which the immune system produces effector and memory T cells is largely unclear. To allow a large-scale assessment of the development of single naive T cells into different subsets, we have developed a technology that introduces unique genetic tags (barcodes) into naive T cells. By comparing the barcodes present in antigen-specific effector and memory T cell populations in systemic and local infection models, at different anatomical sites, and for TCR–pMHC interactions of different avidities, we demonstrate that under all conditions tested, individual naive T cells yield both effector and memory CD8+ T cell progeny. This indicates that effector and memory fate decisions are not determined by the nature of the priming antigen-presenting cell or the time of T cell priming. Instead, for both low and high avidity T cells, individual naive T cells have multiple fates and can differentiate into effector and memory T cell subsets.

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