A NOVEL CELL TYPE CARRYING BOTH Th AND Tc/s MARKERS IN THE BLOOD OF CYCLOSPORINE-TREATED, ALLOGRAFTED RATS

Godden, Urma; Herbert, Jeff; Stewart, Robert D.; Roser, Bruce

doi:10.1097/00007890-198506000-00010

Cited by 22 publications

(11 citation statements)

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“…Following transplantation, only a single study has described them in organ biopsies, but not formally demonstrated coexpression of CD4 and CD8 (37). In animal transplantation models, only one study has found such cells in the periphery associated with cyclosporin A treatment (38).…”

Section: Discussionmentioning

confidence: 99%

Isolation of Human CD4/CD8 Double-Positive, Graft-Versus-Host Disease–Protective, Minor Histocompatibility Antigen–Specific Regulatory T Cells and of a Novel HLA-DR7–Restricted HY-Specific CD4 Clone

Eljaafari

Yuruker

Ferrand

et al. 2013

The Journal of Immunology

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Minor histocompatibility (H) Ags are classically described as self-peptides derived from intracellular proteins that are expressed at the cell surface by MHC class I and class II molecules and that induce T cell alloresponses. We have isolated three different T cell populations from a skin biopsy of a patient suffering from acute graft-versus-host disease following sex-mismatched HLA-identical bone marrow transplantation. The first population was: 1) CD4+/CD8+ double-positive; 2) specific for an HLA class I–restricted autosomal Ag; 3) expressed a Tr1 profile with high levels of IL-10, but low IL-2 and IFN-γ; and 4) exerted regulatory function in the presence of recipient APCs. The second was CD8 positive, specific for an HLA class I–restricted autosomally encoded minor H Ag, but was only weakly cytotoxic. The third was CD4 single positive, specific for an HLA-DR7–restricted HY epitope and exerted both proliferative and cytotoxic functions. Identification of the peptide recognized by these latter cells revealed a new human HY epitope, TGKIINFIKFDTGNL, encoded by RPS4Y and restricted by HLA-DR7. In this paper, we show human CD4/CD8 double-positive, acute graft-versus-host disease–protective, minor H Ag–specific regulatory T cells and identify a novel HLA-DR7/ HY T cell epitope, encoded by RPS4Y, a potential new therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Isolation of Human CD4/CD8 Double-Positive, Graft-Versus-Host Disease–Protective, Minor Histocompatibility Antigen–Specific Regulatory T Cells and of a Novel HLA-DR7–Restricted HY-Specific CD4 Clone

Eljaafari

Yuruker

Ferrand

et al. 2013

The Journal of Immunology

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“…In a variety of conditions, including organ transplantation, 24 a premature exit of the thymus of DP cells has been reported; however, the presence of these cells in our model was small, discarding changes in the hematothymic barrier. 10 We also ruled out an augmented extrathymic T-cell differentiation by determining TCR þ CD8aa lymphocytes, whose peripheral proportion had been reported to increase in some pathological situations, including liver injury.…”

Section: Discussionmentioning

confidence: 69%

Both tacrolimus and sirolimus decrease Th1/Th2 ratio, and increase regulatory T lymphocytes in the liver after ischemia/reperfusion

Arias-Dı́az

Ildefonso

Múñoz

et al. 2009

Laboratory Investigation

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The protective effects of immunosuppressants against ischemia/reperfusion (I/R) injury have been attributed to their non-specific anti-inflammatory effect. However, these effects may also depend on their effect on T lymphocytes, which are increasingly considered to be key players in I/R. Here, we studied the effects of tacrolimus and sirolimus on lymphocyte subpopulations in an I/R rat model. The animals were treated with tacrolimus, sirolimus or vehicle, before undergoing a 60-min ischemia event of the right hepatic lobe, followed by excision of the remaining liver. After 2 h, I/R rats showed increased mortality, plasma lactate dehydrogenase (LDH) levels, hepatocyte apoptosis, liver histological injury and parenchymal infiltration by neutrophils, macrophages, NK cells and T lymphocytes. Most of the changes were antagonized by both immunosuppressants. Tacrolimus augmented the proportion of cycling cells in I/R rats, whereas sirolimus showed the opposite effect. The increased Th1/Th2 ratio found in I/R livers after 2 h was reverted by immunosuppressants, which also amplified the proportion of CD4 þ CD25 þ Foxp3 þ regulatory T lymphocytes at 24 h. The protective effects of both tacrolimus and sirolimus correlated well with a decreased ratio of proinflammatory to anti-inflammatory T lymphocytes, and with an increase in the Treg proportion. This suggests a new mechanism to explain the known beneficial effect shown by immunosuppressants early after I/R.

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“…who reported no effect of thymectomy on the number of rat double positive T cells. 17 This discrepancy may be explained as they analysed double positive T cells participating in an alloresponse in cyclosporine‐treated heart allografted animals, whilst in the present study, the global population of double positive T cells in untreated animals was analysed. Thymectomy did not eliminate rat double positive T cells, as described in humans; 15 approximately half remained.…”

Section: Discussionmentioning

confidence: 85%

“…However, it is becoming increasingly recognized that these distinctions are not so clear cut, with reports in the literature of cytotoxic CD4 + T cells, 1 non‐cytotoxic CD8 + T cells 2 and T cells that express both CD4 and CD8. 3–18 Double positive cells have been observed in vitro following activation of human, 3,4 swine 5,6 and rat 7,8 T cells and also in vivo in healthy humans 3,9 , 10 and swine 5,11 . Their frequency is increased during conditions where the immune system is activated: bacterial infection in mice 12 and humans, 13 viral infection in humans, 9 hapten‐carrier primed rats, 14 autoimmune disease 9,15 , 16 and after transplantation in rats 17 and humans.…”

Section: Introductionmentioning

confidence: 99%

Phenotypic analysis of peripheral CD4⁺ CD8⁺ T cells in the rat

et al. 2000

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SUMMARYAmong peripheral T cells, the expression of CD4 and CD8 is almost mutually exclusive. However, here we show, using¯ow cytometric analysis, that ex vivo approximately 6% of rat T cells stained for both CD4 and CD8. These double positive cells were also detected by confocal microscopy. Only around 50% of double positive cells expressed the CD8b chain, the remaining cells expressed the CD8a chain alone. Double positive cells were blast-like with a phenotype, distinct from that of either CD4 or CD8 single positive cells, suggestive of an activated state. Previous reports of double positive T cells have also suggested that coexpression of CD4 and CD8 is linked to the activation state of the cell. There was an indication that priming animals with a hapten-carrier complex increased the ratio of CD8aa : ab expressing double positive T cells, although we did not detect an increase in the frequency of double positive T cells following priming. We also show that the frequency of double positive cells was reduced following thymectomy and with age. In conclusion, these studies show that peripheral T cells expressing both CD4 and CD8 can be detected in the rat and that they are phenotypically distinct from CD4 and CD8 single positive T cells.

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A NOVEL CELL TYPE CARRYING BOTH Th AND Tc/s MARKERS IN THE BLOOD OF CYCLOSPORINE-TREATED, ALLOGRAFTED RATS

Cited by 22 publications

References 0 publications

Isolation of Human CD4/CD8 Double-Positive, Graft-Versus-Host Disease–Protective, Minor Histocompatibility Antigen–Specific Regulatory T Cells and of a Novel HLA-DR7–Restricted HY-Specific CD4 Clone

Isolation of Human CD4/CD8 Double-Positive, Graft-Versus-Host Disease–Protective, Minor Histocompatibility Antigen–Specific Regulatory T Cells and of a Novel HLA-DR7–Restricted HY-Specific CD4 Clone

Both tacrolimus and sirolimus decrease Th1/Th2 ratio, and increase regulatory T lymphocytes in the liver after ischemia/reperfusion

Phenotypic analysis of peripheral CD4⁺ CD8⁺ T cells in the rat

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A NOVEL CELL TYPE CARRYING BOTH Th AND Tc/s MARKERS IN THE BLOOD OF CYCLOSPORINE-TREATED, ALLOGRAFTED RATS

Cited by 22 publications

References 0 publications

Isolation of Human CD4/CD8 Double-Positive, Graft-Versus-Host Disease–Protective, Minor Histocompatibility Antigen–Specific Regulatory T Cells and of a Novel HLA-DR7–Restricted HY-Specific CD4 Clone

Isolation of Human CD4/CD8 Double-Positive, Graft-Versus-Host Disease–Protective, Minor Histocompatibility Antigen–Specific Regulatory T Cells and of a Novel HLA-DR7–Restricted HY-Specific CD4 Clone

Both tacrolimus and sirolimus decrease Th1/Th2 ratio, and increase regulatory T lymphocytes in the liver after ischemia/reperfusion

Phenotypic analysis of peripheral CD4+ CD8+ T cells in the rat

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Phenotypic analysis of peripheral CD4⁺ CD8⁺ T cells in the rat