scholarly journals Persistent expansions of CD4+ CD8+ peripheral blood T cells

Blood ◽  
1993 ◽  
Vol 82 (5) ◽  
pp. 1546-1552 ◽  
Author(s):  
P Sala ◽  
E Tonutti ◽  
C Feruglio ◽  
F Florian ◽  
A Colombatti
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Blot Hybridization ◽  
Southern Blot Hybridization ◽  
Cell Receptor ◽  
Cd8 Cells ◽  
Hla Dr ◽  
T Cell Receptor Beta

Abstract CD4+ CD8+ cells are present during T cell differentiation in the thymus. Less than 2% of normal T cells that coexpress CD4 and CD8 also are released in the circulation and are present in the peripheral blood. In this study, nine individuals are described that manifested persistent expansions (11% to 43%) of circulating CD4+ CD8+ T cells that in three cases had large granular lymphocyte (LGL) morphology in the absence of either lymphocytosis or overt lymphoproliferative disorders. Southern blot hybridization of enriched CD4+ CD8+ cells with T-cell receptor beta (TCR beta) and TCR gamma probes showed that most cases had the 12-kb Eco RI germinal band deleted or of decreased intensity. In several individuals new TCR beta-specific bands of different intensity and distinct from case to case suggested either monoclonal or oligoclonal and polyclonal expansions. Immunophenotypic analysis showed that in 7 out of 9 cases the CD4+ CD8+ T cells presented with CD8 dim expression. Furthermore, all the CD4+ CD8+ cells did not express many of the known activation antigens (low or absent CD25, CD38, CD71, HLA-DR), whereas they expressed high levels of CD2, CD29, CD56, and CD57. In addition, the CD4+ CD8+ cells of 5 out of 9 subjects coexpressed CD45RA and CD45RO suggesting that these cells might be “frozen” in an intermediate state between naive and memory T cells. In conclusion, the present CD4+ CD8+ cases fall within a larger spectrum of disorders ranging from apparently normal to reactive or proliferative situations and encompassing cells with LGL morphology or LGL-associated antigens expression either in the presence or in the absence of absolute lymphocytosis that deserve careful follow-up investigations.

scholarly journals Persistent expansions of CD4+ CD8+ peripheral blood T cells

Blood ◽  
1993 ◽  
Vol 82 (5) ◽  
pp. 1546-1552 ◽  
Author(s):  
P Sala ◽  
E Tonutti ◽  
C Feruglio ◽  
F Florian ◽  
A Colombatti
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Blot Hybridization ◽  
Southern Blot Hybridization ◽  
Cell Receptor ◽  
Cd8 Cells ◽  
Hla Dr ◽  
T Cell Receptor Beta

CD4+ CD8+ cells are present during T cell differentiation in the thymus. Less than 2% of normal T cells that coexpress CD4 and CD8 also are released in the circulation and are present in the peripheral blood. In this study, nine individuals are described that manifested persistent expansions (11% to 43%) of circulating CD4+ CD8+ T cells that in three cases had large granular lymphocyte (LGL) morphology in the absence of either lymphocytosis or overt lymphoproliferative disorders. Southern blot hybridization of enriched CD4+ CD8+ cells with T-cell receptor beta (TCR beta) and TCR gamma probes showed that most cases had the 12-kb Eco RI germinal band deleted or of decreased intensity. In several individuals new TCR beta-specific bands of different intensity and distinct from case to case suggested either monoclonal or oligoclonal and polyclonal expansions. Immunophenotypic analysis showed that in 7 out of 9 cases the CD4+ CD8+ T cells presented with CD8 dim expression. Furthermore, all the CD4+ CD8+ cells did not express many of the known activation antigens (low or absent CD25, CD38, CD71, HLA-DR), whereas they expressed high levels of CD2, CD29, CD56, and CD57. In addition, the CD4+ CD8+ cells of 5 out of 9 subjects coexpressed CD45RA and CD45RO suggesting that these cells might be “frozen” in an intermediate state between naive and memory T cells. In conclusion, the present CD4+ CD8+ cases fall within a larger spectrum of disorders ranging from apparently normal to reactive or proliferative situations and encompassing cells with LGL morphology or LGL-associated antigens expression either in the presence or in the absence of absolute lymphocytosis that deserve careful follow-up investigations.

scholarly journals Increased frequency of T cell receptor V alpha 12.1 expression on CD8+ T cells: evidence that V alpha participates in shaping the peripheral T cell repertoire.

1991 ◽  
Vol 174 (3) ◽  
pp. 639-648 ◽  
Author(s):  
H DerSimonian ◽  
H Band ◽  
M B Brenner
Keyword(s):  
T Cells ◽  
T Cell ◽  
Gene Product ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Cell Receptor ◽  
Class I ◽  
Class I Mhc ◽  
Alpha Gene

The T cell receptor repertoire has a potential for vast diversity. However, this diversity is limited by the fact that the majority of thymocytes die as the repertoire is shaped by positive and negative selection events during development. Such thymic selection affecting TCR V beta gene segment usage has been demonstrated in the mouse. However, similar data has not been forthcoming in man, and little is known about the role of the TCR alpha chain in antigen/major histocompatibility complex (MHC) recognition in any species. Here, we used a monoclonal antibody recognizing the TCR V alpha 12.1 gene product to assess the expression of this gene in the peripheral blood of man. In most individuals tested, the percentage of cells expressing V alpha 12.1 was significantly higher in CD8+ T cells than in CD4+ T cells. That the V alpha gene product itself was responsible for this increased expression in CD8+ T cells was underscored by the lack of substantial skewing of V beta usage in the V alpha 12.1-bearing T cells. Moreover, the skewed expression of V alpha 12.1 was already present at birth, indicating that it was likely to be due to a developmental process rather than the result of exposure to environmental antigens. Based on the established role for CD8 in binding to class I MHC molecules, we suggest that increased expression of V alpha 12.1 on CD8+ T cells points to a role for TCR's using V alpha 12.1 in class I MHC/Ag recognition. These results indicate that V alpha gene usage in the peripheral blood of man is not random, and they support a role for V alpha as a participant in the self-MHC recognition process that shapes the TCR repertoire.

scholarly journals CD8+ T cells with characteristic T cell receptor beta motif are detected in blood and expanded in synovial fluid of ankylosing spondylitis patients

Rheumatology ◽  
2018 ◽  
Vol 57 (6) ◽  
pp. 1097-1104 ◽  
Author(s):  
Ekaterina A Komech ◽  
Mikhail V Pogorelyy ◽  
Evgeniy S Egorov ◽  
Olga V Britanova ◽  
Denis V Rebrikov ◽  
...  
Keyword(s):  
T Cells ◽  
Ankylosing Spondylitis ◽  
T Cell ◽  
Synovial Fluid ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Cell Receptor ◽  
T Cell Receptor Beta ◽  
Receptor Beta

scholarly journals Pathogenesis of an Infectious Mononucleosis-like Disease Induced by a Murine γ-Herpesvirus: Role for a Viral Superantigen?

1997 ◽  
Vol 185 (9) ◽  
pp. 1641-1650 ◽  
Author(s):  
Ralph A. Tripp ◽  
Ann Marie Hamilton-Easton ◽  
Rhonda D. Cardin ◽  
Phuong Nguyen ◽  
Frederick G. Behm ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Mhc Class Ii ◽  
Infectious Mononucleosis ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Cell Receptor ◽  
Class Ii ◽  
Congenic Mice

The murine γ-herpesvirus 68 has many similarities to EBV, and induces a syndrome comparable to infectious mononucleosis (IM). The frequency of activated CD8+ T cells (CD62Llo) in the peripheral blood increased greater than fourfold by 21 d after infection of C57BL/6J (H-2b) mice, and remained high for at least a further month. The spectrum of T cell receptor usage was greatly skewed, with as many as 75% of the CD8+ T cells in the blood expressing a Vβ4+ phenotype. Interestingly, the Vβ4 dominance was also seen, to varying extents, in H-2k, H-2d, H-2u, and H-2q strains of mice. In addition, although CD4 depletion from day 11 had no effect on the Vβ4 bias of the T cells, the Vβ4+CD8+ expansion was absent in H-2IAb–deficient congenic mice. However, the numbers of cycling cells in the CD4 antibody–depleted mice and mice that are CD4 deficient as a consequence of the deletion of MHC class II, were generally lower. The findings suggest that the IM-like disease is driven both by cytokines provided by CD4+ T cells and by a viral superantigen presented by MHC class II glycoproteins to Vβ4+CD8+ T cells.

scholarly journals Anti-PD-1/PD-L1 Based Combination Immunotherapy to Boost Antigen-Specific CD8+ T Cell Response in Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1922
Author(s):  
Julia Peña-Asensio ◽  
Henar Calvo ◽  
Miguel Torralba ◽  
Joaquín Miquel ◽  
Eduardo Sanz-de-Villalobos ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Receptor ◽  
T Cell Response ◽  
Immune Checkpoints ◽  
Tumor Resistance ◽  
Cell Reactivity ◽  
Precursor Pool ◽  
Cd8 Cells

Thirty to fifty percent of hepatocellular carcinomas (HCC) display an immune class genetic signature. In this type of tumor, HCC-specific CD8 T cells carry out a key role in HCC control. Those potential reactive HCC-specific CD8 T cells recognize either HCC immunogenic neoantigens or aberrantly expressed host’s antigens, but they become progressively exhausted or deleted. These cells express the negative immunoregulatory checkpoint programmed cell death protein 1 (PD-1) which impairs T cell receptor signaling by blocking the CD28 positive co-stimulatory signal. The pool of CD8 cells sensitive to anti-PD-1/PD-L1 treatment is the PD-1dim memory-like precursor pool that gives rise to the effector subset involved in HCC control. Due to the epigenetic imprints that are transmitted to the next generation, the effect of PD-1 blockade is transient, and repeated treatments lead to tumor resistance. During long-lasting disease, besides the TCR signaling impairment, T cells develop other failures that should be also set-up to increase T cell reactivity. Therefore, several PD-1 blockade-based combinatory therapies are currently under investigation such as adding antiangiogenics, anti-TGFβ1, blockade of other negative immune checkpoints, or increasing HCC antigen presentation. The effect of these combinations on CD8+ T cells is discussed in this review.

Effects of rhIL-7 administration in humans on in vivo expansion of naïve, memory and effector subsets of CD4+ & CD8+ T-cells

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2504-2504
Author(s):  
C. Sportes ◽  
F. Hakim ◽  
M. Krumlauf ◽  
R. Babb ◽  
T. Fleisher ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
T Cell Subsets ◽  
Down Regulation ◽  
Cd8 Cells ◽  
Interleukin 7 ◽  
Circulating Cells

2504 Background: IL-7 has a critical and non-redundant role in T-cell lymphopoiesis and peripheral T-cell homeostasis. IL-7 administration may prove clinically valuable in conditions of disease induced (HIV) or iatrogenic T-cell depletion and for modulation of vaccine immune responses. In the first phase I study in humans, recombinant human interleukin-7 (“CYT 99–007”, Cytheris Inc., Rockville, MD) was administered subcutaneously every other day for two weeks in adults with refractory malignancies at 3, 10, 30 and 60 μg/kg/dose. Biologic activity, defined as a 50% increase over baseline of peripheral blood CD3+ T-cells, was seen at and above the 10μg/kg/dose in all patients. The kinetics of proliferation and expansion of peripheral blood T-cell subsets were analyzed. Methods: Multicolor flow cytometry was performed at baseline, 1, 2 and 3 weeks. Among CD4+ cells, the most naïve were defined as CD45RA+ /CD31+. Among CD4+ & CD8+ cells, the main naïve, memory and effector populations were defined respectively as CD45RA+/CD27+, CD45RA-/CD27+ and CD45RA-/CD27-. Within each subset, the number of cells in cycle was defined by Ki67 staining. Results: Following IL-7 therapy, there was marked proliferation of all T-cells subsets, peaking at week 1, most striking for the naive subsets with 30–70% of circulating cells induced to cycle. Proliferation rates were halved by week 2 despite continuation of treatment, coincident with the observed down-regulation of the IL-7 receptor. Cycling returned to baseline by week 3. Significant proliferation was also induced in effector and memory CD4+ and CD8+ T-cells but to a lesser magnitude, resulting in a greater net expansion of the naïve subsets, still ongoing one week after the end of treatment. Conclusions: IL-7 administration induces marked expansion of naïve, memory and effector CD4+ & CD8+ T-cells in humans. Consistent with the known down-regulation of the IL-7 receptor upon IL-7 exposure, proliferation rates decrease during the second week of treatment. rhIL-7 induced T-cell expansion may prove clinically valuable in adoptive immunotherapy as an adjunct to tumor vaccination and / or immunorestorative agent. [Table: see text]

scholarly journals Human fetuses are able to mount an adultlike CD8 T-cell response

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2153-2158 ◽  
Author(s):  
Emmanuel Hermann ◽  
Carine Truyens ◽  
Cristina Alonso-Vega ◽  
Jos Even ◽  
Patricia Rodriguez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Interferon Γ ◽  
T Cell Response ◽  
Activation Markers ◽  
T Cell Receptor Beta

Abstract Fetal/neonatal immune responses generally are considered to be immature and weaker than that of adults. We have studied the cord-blood T cells of newborns congenitally infected with Trypanosoma cruzi, the protozoan agent of Chagas disease. Our data demonstrate a predominant activation of CD8 T cells expressing activation markers and armed to mediate effector functions. The analysis of the T-cell receptor beta chain variable repertoire shows the oligoclonal expansion of these T lymphocytes, indicating that activation was driven by parasite antigens. Indeed, we have detected parasite-specific CD8 T cells secreting interferon-γ after coincubation with live T cruzi. This response is enhanced in the presence of recombinant interleukin-15, which limits the T-cell spontaneous apoptosis. These findings point out that the fetal immune system is more competent than previously appreciated, since fetuses exposed to live pathogens are able to develop an adultlike immune CD8 T-cell response.

scholarly journals Premature Expression of T Cell Receptor (Tcr)αβ Suppresses Tcrγδ Gene Rearrangement but Permits Development of γδ Lineage T Cells

2000 ◽  
Vol 192 (4) ◽  
pp. 537-548 ◽  
Author(s):  
Kathleen Terrence ◽  
Christian P. Pavlovich ◽  
Errin O. Matechak ◽  
B.J. Fowlkes
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Gene Rearrangement ◽  
T Cell Development ◽  
Cell Receptor ◽  
Lineage Commitment ◽  
Cd8 Cells

The T cell receptor (TCR)γδ and the pre-TCR promote survival and maturation of early thymocyte precursors. Whether these receptors also influence γδ versus αβ lineage determination is less clear. We show here that TCRγδ gene rearrangements are suppressed in TCRαβ transgenic mice when the TCRαβ is expressed early in T cell development. This situation offers the opportunity to examine the outcome of γδ versus αβ T lineage commitment when only the TCRαβ is expressed. We find that precursor thymocytes expressing TCRαβ not only mature in the αβ pathway as expected, but also as CD4−CD8− T cells with properties of γδ lineage cells. In TCRαβ transgenic mice, in which the transgenic receptor is expressed relatively late, TCRγδ rearrangements occur normally such that TCRαβ+CD4−CD8− cells co-express TCRγδ. The results support the notion that TCRαβ can substitute for TCRγδ to permit a γδ lineage choice and maturation in the γδ lineage. The findings could fit a model in which lineage commitment is determined before or independent of TCR gene rearrangement. However, these results could be compatible with a model in which distinct signals bias lineage choice and these signaling differences are not absolute or intrinsic to the specific TCR structure.

scholarly journals Human fetuses are able to mount an adultlike CD8 T-cell response

Blood ◽  
2002 ◽  
Vol 100 (6) ◽  
pp. 2153-2158
Author(s):  
Emmanuel Hermann ◽  
Carine Truyens ◽  
Cristina Alonso-Vega ◽  
Jos Even ◽  
Patricia Rodriguez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
Interferon Γ ◽  
T Cell Response ◽  
Activation Markers ◽  
T Cell Receptor Beta

Fetal/neonatal immune responses generally are considered to be immature and weaker than that of adults. We have studied the cord-blood T cells of newborns congenitally infected with Trypanosoma cruzi, the protozoan agent of Chagas disease. Our data demonstrate a predominant activation of CD8 T cells expressing activation markers and armed to mediate effector functions. The analysis of the T-cell receptor beta chain variable repertoire shows the oligoclonal expansion of these T lymphocytes, indicating that activation was driven by parasite antigens. Indeed, we have detected parasite-specific CD8 T cells secreting interferon-γ after coincubation with live T cruzi. This response is enhanced in the presence of recombinant interleukin-15, which limits the T-cell spontaneous apoptosis. These findings point out that the fetal immune system is more competent than previously appreciated, since fetuses exposed to live pathogens are able to develop an adultlike immune CD8 T-cell response.

scholarly journals Characterization of Human CD8 T Cell Responses in Dengue Virus-Infected Patients from India

2016 ◽  
Vol 90 (24) ◽  
pp. 11259-11278 ◽  
Author(s):  
Anmol Chandele ◽  
Jaturong Sewatanon ◽  
Sivaram Gunisetty ◽  
Mohit Singla ◽  
Nattawat Onlamoon ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dengue Virus ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Tcr Signaling ◽  
Hla Dr ◽  
Ifn Γ

ABSTRACT Epidemiological studies suggest that India has the largest number of dengue virus infection cases worldwide. However, there is minimal information about the immunological responses in these patients. CD8 T cells are important in dengue, because they have been implicated in both protection and immunopathology. Here, we provide a detailed analysis of HLA-DR + CD38 + and HLA-DR − CD38 + effector CD8 T cell subsets in dengue patients from India and Thailand. Both CD8 T cell subsets expanded and expressed markers indicative of antigen-driven proliferation, tissue homing, and cytotoxic effector functions, with the HLA-DR + CD38 + subset being the most striking in these effector qualities. The breadth of the dengue-specific CD8 T cell response was diverse, with NS3-specific cells being the most dominant. Interestingly, only a small fraction of these activated effector CD8 T cells produced gamma interferon (IFN-γ) when stimulated with dengue virus peptide pools. Transcriptomics revealed downregulation of key molecules involved in T cell receptor (TCR) signaling. Consistent with this, the majority of these CD8 T cells remained IFN-γ unresponsive even after TCR-dependent polyclonal stimulation (anti-CD3 plus anti-CD28) but produced IFN-γ by TCR-independent polyclonal stimulation (phorbol 12-myristate 13-acetate [PMA] plus ionomycin). Thus, the vast majority of these proliferating, highly differentiated effector CD8 T cells probably acquire TCR refractoriness at the time the patient is experiencing febrile illness that leads to IFN-γ unresponsiveness. Our studies open novel avenues for understanding the mechanisms that fine-tune the balance between CD8 T cell-mediated protective versus pathological effects in dengue. IMPORTANCE Dengue is becoming a global public health concern. Although CD8 T cells have been implicated both in protection and in the cytokine-mediated immunopathology of dengue, how the balance is maintained between these opposing functions remains unknown. We comprehensively characterized CD8 T cell subsets in dengue patients from India and Thailand and show that these cells expand massively and express phenotypes indicative of overwhelming antigenic stimulus and tissue homing/cytotoxic-effector functions but that a vast majority of them fail to produce IFN-γ in vitro . Interestingly, the cells were fully capable of producing the cytokine when stimulated in a T cell receptor (TCR)-independent manner but failed to do so in TCR-dependent stimulation. These results, together with transcriptomics, revealed that the vast majority of these CD8 T cells from dengue patients become cytokine unresponsive due to TCR signaling insufficiencies. These observations open novel avenues for understanding the mechanisms that fine-tune the balance between CD8-mediated protective versus pathological effects.

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