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

Abstract

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.

Attenuation of graft‐versus‐host‐disease in NOD scid IL‐2Rγ−/− (NSG) mice by ex vivo modulation of human CD4+ T cells

“…1 /CD8 1 DP T cells play a crucial role in various pathologies such as cancer and autoimmune disorders and Eljaafari et al studied their protective effects in GvHD (36,37). We also see CD4…”

CD3+CD4negCD8neg (double negative) T lymphocytes and NKT cells as the main cytotoxic-related-CD107a+ cells in lesions of cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis

“…Interpreting data obtained from these two analyses led us to suggest that the NKT-cell pool had the largest portion of their cells dedicated to cytotoxicity, while DN T lymphocytes represent the most prevalent cell population looking to all CD107a + , degranulating cells. DP T cells with regulatory functions were observed in normal tissue and multiple sclerosis skin lesion [33, 34]. However, the recruitment of these cells to the skin is not fully elucidated, and in the periphery, these cells seem to exist as a mature population.…”

CD4+/CD8+ double-positive T cells: more than just a developmental stage?

“…The ability of CD4/CD8 DP T cells to produce IL-10 and IFN-g but not IL-4 has been confirmed by another group, who likewise showed that mouse splenic CD4/CD8 DP T cells can exhibit a suppressive phenotype [38] and reduce T cell proliferation when cocultured with CD4 + T cells. In contrast, a study focusing on human skin biopsies from a GVHD patient reported the ability of CD4/CD8 DP T cells to produce IL-4 [37]; however, a possible regulatory function for these cells was upheld, based on their cytokine-secretion profile, which included IL-10, IFN-g, and TGF-b. CD4/CD8 DP T cells added to a MLR decreased total CD3 + T cell proliferation in a dose-dependent manner, further supporting a suppressive role for CD4/CD8 DP T cells [37].…”

“…In contrast, a study focusing on human skin biopsies from a GVHD patient reported the ability of CD4/CD8 DP T cells to produce IL-4 [37]; however, a possible regulatory function for these cells was upheld, based on their cytokine-secretion profile, which included IL-10, IFN-g, and TGF-b. CD4/CD8 DP T cells added to a MLR decreased total CD3 + T cell proliferation in a dose-dependent manner, further supporting a suppressive role for CD4/CD8 DP T cells [37].…”