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Rare development of Foxp3+ thymocytes in the CD4+CD8+ subset.

ABSTRACT: The CD4(+)CD8(+) (double positive, DP) stage of thymic development is thought to be the earliest period that generates natural Foxp3(+) regulatory T (Treg) cells important for the prevention of autoimmunity. However, we found that most Foxp3(+) DP cells identified by routine flow cytometry represent doublets comprised of Foxp3(-) DP and Foxp3(+) CD4(+)CD8(-) (CD4SP) cells. This was determined using analysis of flow cytometric height and width parameters, postsort contaminants, and thymocyte mixing studies. Temporal analysis of Treg cell development arising from bone marrow precursors in neonatal bone marrow chimeras suggested that Foxp3(+) DP cells are not a major percentage of Foxp3(+) thymocytes, and it supported the notion that most Treg cell development occurred at the immature HSA(high) CD4SP stage. Thus, these data demonstrate that the frequency of Foxp3(+) cells generated at the DP stage is much smaller than previously recognized, suggesting that additional thymocyte maturation may be required to facilitate efficient induction of Foxp3.

SUBMITTER: Lee HM

PROVIDER: S-EPMC2912293 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Rare development of Foxp3+ thymocytes in the CD4+CD8+ subset.

Lee Hyang Mi HM Hsieh Chyi-Song CS

Journal of immunology (Baltimore, Md. : 1950) 20090720 4

The CD4(+)CD8(+) (double positive, DP) stage of thymic development is thought to be the earliest period that generates natural Foxp3(+) regulatory T (Treg) cells important for the prevention of autoimmunity. However, we found that most Foxp3(+) DP cells identified by routine flow cytometry represent doublets comprised of Foxp3(-) DP and Foxp3(+) CD4(+)CD8(-) (CD4SP) cells. This was determined using analysis of flow cytometric height and width parameters, postsort contaminants, and thymocyte mixi ...[more]

PMID: 19620303

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Project description:The outcome of untreated HIV-1 infection is progression to AIDS and death in nearly all cases. Some important exceptions are the small number of patients infected with HIV-1 deleted for the accessory gene, nef. With these infections, disease progression is entirely suppressed or greatly delayed. Whether Nef is critical for high levels of replication or is directly cytotoxic remains controversial. The major problem in determining the role of Nef in HIV/AIDS has been the lack of tractable in vivo models where Nef's complex pathogenic phenotype can be recapitulated.Intravenous inoculation (3000 to 600,000 TCIU) of BLT humanized mice with HIV-1LAI reproducibly establishes a systemic infection. HIV-1LAI (LAI) replicates to high levels (peak viral load in blood 8,200,000?±?1,800,000 copies of viral RNA/ml, range 3,600,000 to 20,400,000; n?=?9) and exhaustively depletes CD4+ T cells in blood and tissues. CD4+CD8+ thymocytes were also efficiently depleted but CD4+CD8- thymocytes were partially resistant to cell killing by LAI. Infection with a nef-deleted LAI (LAINefdd) gave lower peak viral loads (1,220,000?±?330,000, range 27,000 to 4,240,000; n?=?17). For fourteen of seventeen LAINefdd-infected mice, there was little to no loss of either CD4+ T cells or thymocytes. Both LAI- and LAINefdd-infected mice had about 8% of total peripheral blood CD8+ T cells that were CD38+HLA-DR+ compared <1% for uninfected mice. Three exceptional LAINefdd-infected mice that lost CD4+ T cells received 600,000 TCIU. All three exhibited peak viral loads over 3,000,000 copies of LAINefdd RNA/ml. Over an extended time course, substantial systemic CD4+ T cell loss was observed for the three mice, but there was no loss of CD4+CD8+ or CD4+CD8- thymocytes.We conclude Nef is necessary for elevated viral replication and as a result indirectly contributes to CD4+ T cell killing. Further, Nef was not necessary for the activation of peripheral blood CD8+ T cells following infection. However, CD4+CD8+ thymocyte killing was dependent on Nef even in cases of elevated LAINefdd replication and T cell loss. This depletion of thymic T cell precursors may be a significant factor in the elevated pathogenicity of CXCR4 trophic HIV-1.

Dataset Information

Rare development of Foxp3+ thymocytes in the CD4+CD8+ subset.

Publications

Rare development of Foxp3+ thymocytes in the CD4+CD8+ subset.

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