Naive and Stem Cell Memory T Cell Subset Recovery Reveals Opposing Reconstitution Patterns in CD4 and CD8 T Cells in Chronic Graft vs. Host Disease

We have analyzed the V beta usage by CD4+ and CD8+ T cells from human immunodeficiency virus (HIV)-infected individuals in response to an in vitro stimulation with the superantigenic erythrogenic toxin A (ETA) of Streptococcus pyogenes. ETA amplifies specifically CD4+ and CD8+ T cells from control donors expressing the V beta 8 and the V beta 12 elements. When peripheral T cells from asymptomatic HIV-infected individuals were stimulated with ETA, there was a complete lack of activation of the V beta 8+ T cell subset, whereas the V beta 12+ T cell subset responded normally to the superantigen. This V beta-specific anergy, which was also observed in response to staphylococcal enterotoxin E (SEE), affected both CD4+ and CD8+ T cells and represented an intrinsic functional defect rather than a specific lack of response to bacterial superantigens since it was also observed after a stimulation with V beta 8 monoclonal antibodies. The V beta 8 anergic T cells did not express interleukin 2 receptors (IL-2Rs) and failed to proliferate in response to exogenous IL-2 or IL-4, suggesting that this anergy was not a reversible process, at least by the use of these cytokines. The unresponsiveness of the V beta 8 T cell subset is frequent since it was found in 56% of the patients studied, and comparison of the clinical status of responder vs. anergic patients indicated that the only known common factor between them was HIV infection. In addition, it is noteworthy that the anergy of the V beta 8 subset may be a very early phenomenon since it was found in a patient at Centers for Disease Control stage I of the disease. These data provide evidence that a dominant superantigen may be involved in the course of HIV infection and that the contribution of HIV has to be considered.

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CXCR5 and ICOS expression identifies a CD8 T-cell subset with TFH features in Hodgkin lymphomas

Blood Advances ◽

10.1182/bloodadvances.2018017244 ◽

2018 ◽

Vol 2 (15) ◽

pp. 1889-1900 ◽

Cited By ~ 10

Author(s):

Kieu-Suong Le ◽

Patricia Amé-Thomas ◽

Karin Tarte ◽

Françoise Gondois-Rey ◽

Samuel Granjeaud ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Subset ◽

Cd8 T Cell ◽

T Cell Subset ◽

Tfh Cells ◽

Key Points ◽

Functional Features

Key Points A subset of CD8 T cells in some Hodgkin lymphomas shares phenotypic and functional features with CD4 TFH cells.

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Interleukin-2 inhibits graft-versus-host disease-promoting activity of CD4+ cells while preserving CD4- and CD8-mediated graft-versus-leukemia effects

Blood ◽

10.1182/blood.v83.9.2560.2560 ◽

1994 ◽

Vol 83 (9) ◽

pp. 2560-2569 ◽

Cited By ~ 67

Author(s):

M Sykes ◽

MW Harty ◽

GL Szot ◽

DA Pearson

Keyword(s):

T Cells ◽

T Cell ◽

Graft Versus Host Disease ◽

Interleukin 2 ◽

Cell Subset ◽

Spleen Cells ◽

Host Disease ◽

Graft Versus Host ◽

T Cell Subset ◽

Graft Versus Leukemia

Abstract We have recently shown that a short course of high-dose interleukin-2 (IL-2) can markedly inhibit the graft-versus-host disease (GVHD)- promoting activity of donor CD4+ T cells. The difficulty in dissociating GVHD-promoting from graft-versus-leukemia (GVL) effects of alloreactive donor T cells currently prevents clinical bone marrow transplantation (BMT) from fulfilling its full potential. To test the capacity of IL-2 treatment to promote such a dissociation, we have developed a new murine transplantable acute myelogenous leukemia model using a class II major histocompatibility complex-positive BALB/c Moloney murine leukemia virus-induced promonocytic leukemia, 2B-4–2. BALB/c mice receiving 2.5 x 10(5) 2B-4–2 cells intravenously 1 week before irradiation and syngeneic BMT died from leukemia within 2 to 4 weeks after BMT. Administration of syngeneic spleen cells and/or a 2.5- day course of IL-2 treatment alone did not inhibit leukemic mortality. In contrast, administration of non-T-cell-depleted fully allogeneic B10 (H-2b) spleen cells and T-cell-depleted B10 marrow led to a significant delay in leukemic mortality in IL-2-treated mice. In these animals GVHD was inhibited by IL-2 treatment. GVL effects were mediated entirely by donor CD4+ and CD8+ T cells. Remarkably, IL-2 administration did not diminish the magnitude of the GVL effect of either T-cell subset. This was surprising, because CD4-mediated GVHD was inhibited in the same animals in which CD4-mediated GVL effects were not reduced by IL-2 treatment. These results suggest a novel mechanism by which GVHD and GVL effects of a single unprimed alloreactive T-cell subset can be dissociated; different CD4 activities promote GVHD and GVL effects, and the former, but not the latter activities are inhibited by treatment with IL-2.

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Thymomas alter the T-cell subset composition in the blood: a potential mechanism for thymoma-associated autoimmune disease

Blood ◽

10.1182/blood.v96.12.3872 ◽

2000 ◽

Vol 96 (12) ◽

pp. 3872-3879 ◽

Cited By ~ 108

Author(s):

Viola Hoffacker ◽

Anja Schultz ◽

James J. Tiesinga ◽

Ralf Gold ◽

Berthold Schalke ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Autoimmune Disease ◽

Cd8 T Cells ◽

Cell Function ◽

Cell Subset ◽

Cell Repertoire ◽

T Cell Subset ◽

Functional Studies ◽

Circulating T Cells

Abstract Thymomas are the only tumors that are proven to generate mature T cells from immature precursors. It is unknown, however, whether intratumorous thymopoiesis has an impact on the peripheral T-cell pool and might thus be related to the high frequency of thymoma-associated myasthenia gravis. This study shows, using fluorescence-activated cell sorting-based analyses and T-cell proliferation assays, that thymopoiesis and T-cell function in thymomas correspond with immunologic alterations in the blood. Specifically, the proportion of circulating CD45RA+CD8+ T cells is significantly increased in patients with thymoma compared with normal controls, in accordance with intratumorous T-cell development that is abnormally skewed toward the CD8+ phenotype. Moreover, it is primarily the proportion of circulating CD45RA+CD8+ T cells that decreases after thymectomy. The results also demonstrate that T cells reactive toward recombinant autoantigens are distributed equally between thymomas and blood, whereas T-cell responses to foreign antigen (ie, tetanus toxoid) are seen only among circulating T cells and not among thymoma-derived T cells. These functional studies support the hypothesis that thymopoiesis occurring within thymomas alters the peripheral T-cell repertoire. Because many thymomas are enriched with autoantigen-specific T cells, a disturbance of circulating T-cell subset composition by export of intratumorous T cells may contribute to paraneoplastic autoimmune disease arising in patients with thymoma.

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Phenotypic and Functional Separation of Memory and Effector Human CD8+ T Cells

Journal of Experimental Medicine ◽

10.1084/jem.186.9.1407 ◽

1997 ◽

Vol 186 (9) ◽

pp. 1407-1418 ◽

Cited By ~ 972

Author(s):

Dörte Hamann ◽

Paul A. Baars ◽

Martin H.G. Rep ◽

Berend Hooibrink ◽

Susana R. Kerkhof-Garde ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Fas Ligand ◽

Cytotoxic T Lymphocyte ◽

Cell Subset ◽

Cd8 T Cell ◽

Cytolytic Activity ◽

T Cell Subset

Human CD8+ memory- and effector-type T cells are poorly defined. We show here that, next to a naive compartment, two discrete primed subpopulations can be found within the circulating human CD8+ T cell subset. First, CD45RA−CD45R0+ cells are reminiscent of memory-type T cells in that they express elevated levels of CD95 (Fas) and the integrin family members CD11a, CD18, CD29, CD49d, and CD49e, compared to naive CD8+ T cells, and are able to secrete not only interleukin (IL) 2 but also interferon γ, tumor necrosis factor α, and IL-4. This subset does not exert cytolytic activity without prior in vitro stimulation but does contain virus-specific cytotoxic T lymphocyte (CTL) precursors. A second primed population is characterized by CD45RA expression with concomitant absence of expression of the costimulatory molecules CD27 and CD28. The CD8+CD45RA+CD27− population contains T cells expressing high levels of CD11a, CD11b, CD18, and CD49d, whereas CD62L (L-selectin) is not expressed. These T cells do not secrete IL-2 or -4 but can produce IFN-γ and TNF-α. In accordance with this finding, cells contained within this subpopulation depend for proliferation on exogenous growth factors such as IL-2 and -15. Interestingly, CD8+CD45RA+CD27− cells parallel effector CTLs, as they abundantly express Fas-ligand mRNA, contain perforin and granzyme B, and have high cytolytic activity without in vitro prestimulation. Based on both phenotypic and functional properties, we conclude that memory- and effector-type T cells can be separated as distinct entities within the human CD8+ T cell subset.

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Human Minor Histocompatibility Antigen-Specific CD8+ T Cells Are Found Predominantly in the CD45RA+ CD62L+ Naïve T Cell Subset.

Blood ◽

10.1182/blood.v106.11.578.578 ◽

2005 ◽

Vol 106 (11) ◽

pp. 578-578 ◽

Cited By ~ 5

Author(s):

Marie Bleakley ◽

Audrey Mollerup ◽

Colette Chaney ◽

Michele Brown ◽

Stanley R. Riddell

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Cell Subset ◽

Target Cells ◽

Screening Assay ◽

Memory T Cell ◽

Alloreactive T Cells ◽

Selective Depletion

Abstract Graft versus host disease (GVHD) after allogeneic stem cell transplant (SCT) is initiated by the activation of alloreactive T cells by host dendritic cells (DC) in lymphoid tissue. Studies in murine models have demonstrated that selective depletion of naïve T cells abrogates GVHD in major and minor histocompatibility antigen (miH) mismatched SCT and provides for rapid reconstitution of memory T cell responses to pathogens. This suggests the memory subset may lack a sufficient repertoire of alloreactive T cells or fail to localize to sites where GVHD is initiated. If such a strategy were effective in humans, morbidity from GVHD would be reduced, but the graft versus leukemia (GVL) effect might be compromised. To explore the potential of this approach in humans, we developed a novel limiting dilution assay using DC as stimulator cells in vitro to analyze the frequency and repertoire of human miH reactive T cells in highly purified naïve and memory T cell subsets obtained from HLA identical volunteer donor pairs. For each pair, mature DC were derived by differentiation of CD14+ monocytes in vitro from one volunteer, and pure (>97%) populations of naïve (CD62L+, CD45 RA+, CD45RO-) and memory (CD45RO+) CD8 T cells were obtained by FACS sorting of CD8 enriched PBMC from the respective HLA identical sibling. Memory and naïve T cells were cultured for 12 days in 96 well plates at a range of concentrations with DC at a 30:1 ratio and IL12 (10 ng/ml), and IL15 (10 ng/ml) was added on day 7. On day 12, the wells were screened against target cells from each volunteer in a chromium release assay (CRA) to quantitative T cells with reactivity against miH. All wells with reactivity in this screening assay were subsequently expanded using anti CD3 antibody and IL2 and retested by CRA to validate the results of the screening assay. In multiple experiments using different HLA matched pairs, T cells with specific and reproducible cytotoxic activity (>15% lysis) against target cells from the DC donor but not autologous targets were only isolated from wells plated with naïve CD8 T cells, and there was no reproducible cytotoxicity from wells plated with memory T cells. This data demonstrates that miH specific CD8 T cells are found predominantly, and possibly exclusively, in the naïve T cell subset in humans. This data is consistent with a dramatically reduced repertoire of miH alloreactive T cells in the memory T cell pool and supports the development of protocols to prevent GVHD by selective depletion of CD45RA+ CD8+ T cells from the hematopoietic cell graft. However, T cells specific for miH also contribute to the GVL effect and CD45RA depletion would be expected to compromise antileukemic activity. Using the above approach for isolating miH specific CTL from naïve CD8 T cells, we have found a diverse repertoire of alloreactivity in most cultures and identified a subset of T cell lines and clones specific for miH presented selectively on hematopoietic cells. These T cells recognize primary ALL and AML samples that express the restricting HLA allele in vitro. MiH specific T cell clones can be reliably generated by this method using DC derived from monocytes of patients with advanced leukemia. Thus, it may be feasible to utilize this approach to isolate T cells specific for hematopoietic restricted miH for adoptive therapy as an adjunct to CD45RA depletion to preserve the GVL effect and allow separation of GVL from GVHD.

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Improved survival from potentially lethal graft-vs.-host disease by donor pretreatment with a recipient-specific blood transfusion. II. Evidence for a principal role of the CD4+ T cell subset

European Journal of Immunology ◽

10.1002/eji.1830230149 ◽

1993 ◽

Vol 23 (1) ◽

pp. 299-302 ◽

Cited By ~ 1

Author(s):

Andre C. Knulst ◽

G. John M. Tibbe ◽

Clara Bril-Bazuin ◽

Robbert Benner

Keyword(s):

T Cell ◽

Blood Transfusion ◽

Cell Subset ◽

Cd4 T Cell ◽

Host Disease ◽

Principal Role ◽

T Cell Subset ◽

Graft Vs Host Disease ◽

Donor Pretreatment

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

Blood ◽

10.1182/blood-2010-10-312751 ◽

2011 ◽

Vol 117 (11) ◽

pp. 3230-3239 ◽

Cited By ~ 29

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.

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