Human CD8+ T-cells Recognizing Peptides from Mycobacterium tuberculosis (Mtb) Presented by HLA-E Have an Unorthodox Th2-like, Multifunctional, Mtb Inhibitory Phenotype and Represent a Novel Human T-cell Subset

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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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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Cytotoxic Activity and Memory T Cell Subset Distribution of in vitro-Stimulated CD8+ T Cells Specific for HER2/neu Epitopes

Frontiers in Immunology ◽

10.3389/fimmu.2019.01017 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 2

Author(s):

Maria Kuznetsova ◽

Julia Lopatnikova ◽

Julia Shevchenko ◽

Alexander Silkov ◽

Amir Maksyutov ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cytotoxic Activity ◽

Cd8 T Cells ◽

Cell Subset ◽

T Cell Subset ◽

Memory T Cell ◽

Subset Distribution

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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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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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Apoptotic Pathways of Human Regulatory T Cells in Chronic Graft Versus Host Disease (cGVHD) After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Blood ◽

10.1182/blood.v120.21.225.225 ◽

2012 ◽

Vol 120 (21) ◽

pp. 225-225

Author(s):

Kazuyuki Murase ◽

Yutaka Kawano ◽

Jeremy Ryan ◽

Ken-ichi Matsuoka ◽

Gregory Bascug ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Low Dose ◽

Cell Subset ◽

Mitochondrial Pathway ◽

T Cell Subsets ◽

T Cell Subset ◽

Mitochondrial Membrane Depolarization

Abstract Abstract 225 CD4+CD25+Foxp3+ regulatory T cells (Treg) are known to play a central role in the maintenance of self-tolerance and immune homeostasis. After allogeneic stem cell transplantation, impaired recovery of Treg is associated with the development of cGVHD. Interleukin-2 (IL-2) is a critical regulator of Treg development, expansion and survival and lack of IL-2 results in Treg deficiency. In patients with cGVHD, we previously demonstrated that Treg proliferate at high levels but this subset is also highly susceptible to apoptosis leading to inadequate Treg numbers (Matsuoka et al. JCI 2010). We also reported that low-dose IL-2 administration resulted in selective expansion of Treg in vivo and clinical improvement of cGVHD (Koreth et al. NEJM 2011). To identify mechanisms responsible for increased Treg susceptibility to apoptosis in cGVHD we used a new flow cytometry-based assay to measure mitochondrial membrane depolarization in response to a panel of pro-apoptotic BH3 peptides (BIM, BID, BAD, NOXA, PUMA, BMF, HRK). This assessment allowed us to compare BH3 peptide-induced mitochondrial membrane depolarization (“priming”) in different T cell subsets, including CD4 Treg, conventional CD4 T cells (CD4 Tcon), and CD8 T cells. Expression of Bcl-2, CD95 and Ki67 were also studied in each T cell subset. We studied peripheral blood samples from 36 patients with hematologic malignancies (median age 59 yr) who are > 2 years post HSCT (27 patients with cGVHD and 9 patients without cGVHD) and 15 patients who received daily subcutaneous IL-2 for 8 weeks for treatment of steroid-refractory cGvHD. Severity of cGVHD was classified according to NIH criteria. In patients without cGVHD, BH3 priming was similar in all 3 T cell subsets (CD4 Treg, CD4 Tcon and CD8). In patients with cGVHD, CD4 Treg were more primed than CD4 Tcon when challenged with BIM, BAD, PUMA, BMF and the combination of BAD + NOXA peptides (p<0.01 – 0.0001). Treg were more primed than CD8 T cells when challenged with PUMA peptide (p<0.0001), but priming in Treg and CD8 T cells was similar for other BH3 peptides in patients with cGVHD. We also compared BH3 priming of each T cell subset in patients with different grades of cGVHD. When challenged with BH3 peptides, Treg, Tcon and CD8 T cells were less primed in patients with severe cGVHD. In patients with cGVHD, Treg expressed higher levels of Ki-67, higher levels of CD95 and lower levels of Bcl-2 than Tcon. Expression of CD95 did not vary with severity of GVHD in any T cell subset, but expression of Bcl-2 was significantly increased in all subsets in patients with severe cGVHD. Increased BH3 priming and high expression of CD95 indicate that Treg are more susceptible to apoptosis than Tcon in cGVHD. However, both Treg and Tcon become less primed and Bcl-2 levels increase in severe cGVHD suggesting that these cells are less susceptible to mitochondrial pathway apoptosis. Since the total number of Treg and Tcon are significantly reduced in patients with cGVHD, these findings suggest that the remaining circulating cells are relatively resistant to mitochondrial pathway apoptosis. CD95 expression in Treg remains high indicating no change in death receptor pathway apoptosis. Daily treatment with low-dose IL-2 for 8 weeks selectively expands Treg in vivo in patients with severe cGVHD. As the number of Treg increase, BH3 profiling shows that these cells gradually become more primed and therefore more susceptible to mitochondrial pathway apoptosis. Taken together, these studies help define the complex and distinct pathways that regulate survival in different T cell subsets and changes in these pathways that occur in patients with chronic GVHD. These pathways play important roles in the maintenance of T cell homeostasis and targeting these complex pathways can provide new opportunities to promote immune tolerance after allogeneic HSCT. Disclosures: No relevant conflicts of interest to declare.

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CD8+CD28-T cells: Certainties and uncertainties of a prevalent human T-cell subset

Immunology and Cell Biology ◽

10.1046/j.1440-1711.2002.01057.x ◽

2002 ◽

Vol 80 (1) ◽

pp. 1-13 ◽

Cited By ~ 54

Author(s):

Fernando A Arosa

Keyword(s):

T Cells ◽

T Cell ◽

Cell Subset ◽

T Cell Subset ◽

Human T Cell

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Thalidomide Costimulates Primary Human T Lymphocytes, Preferentially Inducing Proliferation, Cytokine Production, and Cytotoxic Responses in the CD8+ Subset

Journal of Experimental Medicine ◽

10.1084/jem.187.11.1885 ◽

1998 ◽

Vol 187 (11) ◽

pp. 1885-1892 ◽

Cited By ~ 399

Author(s):

Patrick A.J. Haslett ◽

Laura G. Corral ◽

Matthew Albert ◽

Gilla Kaplan

Keyword(s):

T Cells ◽

T Cell ◽

Interleukin 2 ◽

Cell Subset ◽

Cell Receptor ◽

T Cell Response ◽

Cytotoxic T Cell ◽

T Cell Subset ◽

Human T Cell

The efficacy of thalidomide (α-phthalimido-glutarimide) therapy in leprosy patients with erythema nodosum leprosum is thought to be due to inhibition of tumor necrosis factor α. In other diseases reported to respond to thalidomide, the mechanism of action of the drug is unclear. We show that thalidomide is a potent costimulator of primary human T cells in vitro, synergizing with stimulation via the T cell receptor complex to increase interleukin 2–mediated T cell proliferation and interferon γ production. The costimulatory effect is greater on the CD8+ than the CD4+ T cell subset. The drug also increases the primary CD8+ cytotoxic T cell response induced by allogeneic dendritic cells in the absence of CD4+ T cells. Therefore, human T cell costimulation can be achieved pharmacologically with thalidomide, and preferentially in the CD8+ T cell subset.

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Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential.

Journal of Experimental Medicine ◽

10.1084/jem.177.3.627 ◽

1993 ◽

Vol 177 (3) ◽

pp. 627-636 ◽

Cited By ~ 314

Author(s):

D Fowell ◽

D Mason

Keyword(s):

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Autoimmune Diabetes ◽

Interleukin 2 ◽

Cell Subset ◽

Cd4 T Cell ◽

Male Rats ◽

Cell Repertoire ◽

T Cell Subset

Diabetes was induced in a normal nonautoimmune rat strain by rendering the animals relatively T cell deficient using a protocol of adult thymectomy and sublethal gamma irradiation. All male rats and 70% of females developed an acute syndrome with severe loss of weight and hyperglycemia. Diabetes in these lymphopoenic rats was associated with extensive insulitis involving CD4+ and CD8+ T cells and macrophages. The CD8+ T cells were essential for the development of diabetes but not insulitis. The autoimmune diabetes and insulitis were completely prevented by the injection of a particular CD4+ T cell subset, isolated from healthy syngeneic donors, of the phenotype CD45RClow T cell receptor alpha/beta+ RT6+ Thy-1- OX-40-. Cells of this protective phenotype, which make up about 5% of thoracic duct lymphocytes, were found to provide help for secondary antibody responses and produce interleukin 2 (IL-2) and IL-4, but no interferon gamma, on in vitro activation. These data provide evidence for the presence of autoreactive T cells in the normal immune system of the rat and reveal that in the intact animal these cells are prevented from expressing their autoreactive potential by other T cells.

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