Human KIR+CD8+ T cells target pathogenic T cells in Celiac disease and are active in autoimmune diseases and COVID-19

Previous reports show that Ly49+CD8+ T cells can suppress autoimmunity in mouse models of autoimmune diseases. Here we find a markedly increased frequency of CD8+ T cells expressing inhibitory Killer cell Immunoglobulin like Receptors (KIR), the human equivalent of the Ly49 family, in the blood and inflamed tissues of various autoimmune diseases. Moreover, KIR+CD8+ T cells can efficiently eliminate pathogenic gliadin-specific CD4+ T cells from Celiac disease (CeD) patients' leukocytes in vitro. Furthermore, we observe elevated levels of KIR+CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 and influenza-infected patients, and this correlates with disease severity and vasculitis in COVID-19. Expanded KIR+CD8+ T cells from these different diseases display shared phenotypes and similar T cell receptor sequences. These results characterize a regulatory CD8+ T cell subset in humans, broadly active in both autoimmune and infectious diseases, which we hypothesize functions to control self-reactive or otherwise pathogenic T cells.

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Human HLA-A*02:01/CHM1+ allo-restricted T cell receptor-transgenic CD8+ T cells specifically inhibit Ewing sarcoma growth in vitro and in vivo

European Journal of Cancer ◽

10.1016/s0959-8049(16)32737-x ◽

2016 ◽

Vol 69 ◽

pp. S51

Author(s):

U. Thiel ◽

F. Blaeschke ◽

G. Richter ◽

S. Burdach

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Ewing Sarcoma ◽

Cell Receptor

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Human HLA-A*02:01/CHM1+ allo-restricted T cell receptor transgenic CD8+ T Cells specifically inhibit Ewing sarcoma growth in vitro and in vivo

Oncotarget ◽

10.18632/oncotarget.9218 ◽

2016 ◽

Vol 7 (28) ◽

pp. 43267-43280 ◽

Cited By ~ 10

Author(s):

Franziska Blaeschke ◽

Uwe Thiel ◽

Andreas Kirschner ◽

Melanie Thiede ◽

Rebeca Alba Rubio ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Ewing Sarcoma ◽

Cell Receptor

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Clonal populations of CD4+ and CD8+ T cells in patients with multiple myeloma and paraproteinemia

Blood ◽

10.1182/blood.v87.8.3297.bloodjournal8783297 ◽

1996 ◽

Vol 87 (8) ◽

pp. 3297-3306 ◽

Cited By ~ 65

Author(s):

P Moss ◽

G Gillespie ◽

P Frodsham ◽

J Bell ◽

H Reyburn

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Gene Segment ◽

Cell Subset ◽

Cell Receptor ◽

T Cell Subsets ◽

Activation Markers ◽

Healthy Elderly

Patients with paraproteinemia have abnormalities in their T-cell subsets including inversion of the CD4:CD8 ratio and increased expression of activation markers. Recently, distortions in T-cell receptor (TCR) TCRAV and TCRBV gene segment expression have been reported, although the significance of these observations is unclear given the finding of clonal populations of CD8+ T cells in healthy elderly individuals. We have used an extensive range of TCR V-region- specific monoclonal antibodies to assess TCRAV and TCRBV expression in patients with myeloma and paraproteinemia. TCR sequence analysis was used to assess the clonality of expansions and 3-color fluorescence- activated cell sorting analysis determined the phenotype of the expanded populations. The patients show novel oligoclonal expansions within the CD4+ subset and show an increased frequency of CD8+ expansions. Oligoclonal CD4+ T cells belong to the rare CD4+CD28- T- cell subset, a phenotype associated with granular morphology. CD45RA and CD11b are expressed on many of the CD8 T-cell expansions. Comparison of T-cell receptor sequences from two T-cell clones in one patient suggests a possible role for a common peptide antigen in the generation of the expansions. Further work is needed to identify the relevance of such T cells to the B-cell proliferation.

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Isolation and Characterization of Human Antigen-Specific TCRαβ+ CD4−CD8− Double Negative Regulatory T Cells.

Blood ◽

10.1182/blood.v106.11.3306.3306 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3306-3306

Author(s):

Karin Fischer ◽

Simon Voelkl ◽

Grzegorz K. Przybylski ◽

Christian A. Schmidt ◽

Reinhard Andreesen ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Proliferative Response ◽

Cell Subset ◽

Cell Receptor ◽

Treg Cells ◽

Double Negative ◽

Isolation And Characterization

Abstract Compelling evidence indicate that regulatory T (Treg) cells play an important role in the maintenance of immune tolerance to self and foreign antigens (Ag). Various subsets of T lymphocytes have been isolated in mice and humans that have the ability to down-regulate the proliferation of autoimmune effector cells. Recently, a novel subset of Ag-specific T-cell receptor (TCR)αβ+ CD4−CD8− (double negative, DN) Treg cells has been found to be able to prevent the rejection of skin and heart allografts by specifically inhibiting the function of anti-graft-specific CD8+ T cells. Here we demonstrate that peripheral DN Treg cells are present in humans, where they constitute about 1% of total CD3+ T cells, and consist of both naïve and Ag-experienced cells. Furthermore, analysis of T-cell receptor excision circles (TRECs) indicate that DN T cells are not recent thymic emigrants, but rather an expanded T-cell subset. MHC multimer staining revelaed a distinct population of DN T cells recognizing common MHC class I-restricted CMV and EBV antigens. DN T cells exhibited a strong proliferative response upon stimulation with allogeneic antigen presenting cells (APC) and secreted high amounts of IFN-γ but no IL-2, with some IL-5, and marginal levels of IL-4 and IL-10. Similar to murine DN Treg cells, human DN Treg cells are able to acquire peptide-HLA-A2 complexes from APCs by cell contact-dependent mechanisms. Furthermore, such acquired peptide-HLA complexes appear to be functionally active, in that CD8+ T cells specific for the HLA-A2-restricted self peptide, Melan-A, became sensitive to apoptosis by neighboring DN T cells after acquisition of Melan-A-HLA-A2 complexes and revealed a reduced proliferative response. These results demonstrate for the first time that a sizeable population of peripheral DN Treg cells exists in humans that are able to suppress Ag-specific T cells. DN Treg cells may serve to limit clonal expansion of allo-Ag-specific T cells after transplantation.

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In vitro generation of mature, naive antigen-specific CD8+ T cells with a single T-cell receptor by agonist selection

Leukemia ◽

10.1038/leu.2013.285 ◽

2013 ◽

Vol 28 (4) ◽

pp. 830-841 ◽

Cited By ~ 13

Author(s):

S Snauwaert ◽

G Verstichel ◽

S Bonte ◽

G Goetgeluk ◽

S Vanhee ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Cell Receptor

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T cell receptor ligation induces interleukin (IL) 2R beta chain expression in rat CD4,8 double positive thymocytes, initiating an IL-2-dependent differentiation pathway of CD8 alpha+/beta- T cells.

Journal of Experimental Medicine ◽

10.1084/jem.177.2.541 ◽

1993 ◽

Vol 177 (2) ◽

pp. 541-546 ◽

Cited By ~ 12

Author(s):

J H Park ◽

R Mitnacht ◽

N Torres-Nagel ◽

T Hünig

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Cd8 T Cells ◽

Cell Receptor ◽

Beta Chain ◽

Double Positive ◽

Alpha Chain ◽

Alpha Beta

The role of interleukin (IL)2 in intrathymic T cell development is highly controversial, and nothing is known about IL-2R expression on thymocytes of the T cell receptor (TCR) alpha/beta lineage undergoing TCR-driven differentiation events. We analyze here IL-2R alpha and beta mRNA expression in an in vitro system where newly generated rat CD4,8 double positive (DP) thymocytes respond to TCR ligation plus IL-2 (but not to either stimulus alone) with rapid differentiation to functional CD8 single positive T cells (Hünig, T., and R. Mitnacht. 1991. J. Exp. Med. 173:561). TCR ligation induced expression of IL-2R beta (but not alpha) chain mRNA in DP thymocytes. Addition of IL-2 then lead to functional maturation and expression of the IL-2R alpha chain. To investigate if the CD8 T cells generated via this IL-2R beta-driven pathway in vitro correspond to the bulk of CD8 T cells seeding peripheral lymphoid organs in vivo, we compared their phenotype to that of lymph node CD8 T cells. Surprisingly, analysis of CD8 cell surface expression using a novel anti-CD8 monoclonal antibody specific for the alpha/beta heterodimeric isoform, and of CD8 alpha and beta chain mRNA revealed that T cells generated by TCR ligation plus IL-2 resemble thymus-independent rather than thymus-derived CD8 cells in that they express CD8 alpha without beta chains. These findings demonstrate that TCR crosslinking induces functional IL-2R on immature DP rat thymocytes. In addition, they show that at least in vitro, CD8 alpha/alpha T cells are generated from TCR-stimulated DP thymocytes (which express the CD8 alpha/beta in the heterodimeric isoform) along an IL-2-driven pathway of T cell differentiation.

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