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1.  Levels of circulating myeloid subpopulations and of heme oxygenase-1 do not predict CD4+ T cell recovery after the initiation of antiretroviral therapy for HIV disease 
The level (or frequency) of circulating monocyte subpopulations such as classical (CD14hiCD16-) and non-classical (CD14dimCD16+) monocytes varies during the course of HIV disease progression and antiretroviral therapy (ART). We hypothesized that such variation and/or differences in the degree to which these cells expressed the immunoregulatory enzyme, heme oxygenase-1 (HO-1), would be associated with CD4+ T cell recovery after the initiation of ART. This hypothesis was tested in a cross-sectional study of four groups of HIV-infected subjects, including those who were seronegative, untreated virologic controllers [detectable viral load (VL) of <1000 copies/mL], untreated virologic non-controllers [VL > 10,000 copies/mL], and ART-mediated virologic controllers [VL < 75 copies/mL]. A longitudinal analysis of ART-treated subjects was also performed along with regression analysis to determine which biomarkers were associated with and/or predictive of CD4+ T cell recovery. Suppressive ART was associated with increased levels of classical monocyte subpopulations (CD14hiCD16-) and decreased levels of non-classical monocyte populations (CD14dimCD16+). Among peripheral blood mononuclear cells (PBMCs), HO-1 was found to be most highly up-regulated in CD14+ monocytes after ex vivo stimulation. Neither the levels of monocyte subpopulations nor of HO-1 expression in CD14+ monocytes were significantly associated with the degree of CD4+ T cell recovery. Monocyte subpopulations and HO-1 gene expression were, however, restored to normal levels by suppressive ART. These results suggest that the level of circulating monocyte subpopulations and their expression of HO-1 have no evident relationship to CD4+ T cell recovery after the initiation of ART.
PMCID: PMC4150425  PMID: 25180041
HIV; HO-1; Immune activation; Monocytes; CD4+ T cell recovery
2.  Fetal Regulatory T Cells and Peripheral Immune Tolerance in utero: Implications for Development and Disease 
The developing fetus must actively learn to tolerate benign antigens, or suffer the consequences of broken tolerance. Tolerance of self-antigens prevents development of autoimmune diseases, and is achieved by both deletion of autoreactive T cell clones in the thymus (central tolerance) and by the suppressive influence of CD4+CD25+FoxP3+ regulatory T cells (Tregs) in the periphery. Fetal CD4+ T cells have a strong predisposition to differentiate into tolerogenic Tregs that actively promote self-tolerance, as well as tolerance to non-inherited antigens on chimeric maternal cells that reside in most fetal tissues. As the fetus nears birth, a crucial transition must occur between the tolerogenic fetal immune system and a more defensive adult-type immune system that is able to combat pathogens. This paper will review the unique tolerogenic nature of the human fetal immune system and will examine evidence for a novel model of fetal immune development: the layered immune system hypothesis.
PMCID: PMC3951896  PMID: 23432802
Fetal T Cells; FoxP3; Human Developmental Immunology; Layered Immune System; Microchimerism; Regulatory T Cells (Treg); Tolerance
3.  Variations in the heme oxygenase-1 microsatellite polymorphism are associated with plasma CD14 and viral load in HIV-infected African Americans 
Genes and Immunity  2011;13(3):258-267.
Heme oxygenase-1 (HO-1) is an anti-inflammatory enzyme that maintains homeostasis during cellular stress. Given previous findings that shorter length variants of a HO-1 promoter-region GTn microsatellite polymorphism are associated with increased HO-1 expression in cell lines, we hypothesized that shorter variants would also be associated with increased levels of HO-1 expression, less inflammation, and lower levels of inflammation-associated viral replication in HIV-infected subjects. Healthy donors (n=20) with shorter GTn repeats had higher HO-1 mRNA transcript in peripheral blood mononuclear cells stimulated with lipopolysaccharide (LPS) (r= −0.38, p=0.05). The presence of fewer GTn repeats in subjects with untreated HIV disease was associated with higher HO-1 mRNA levels in peripheral blood (r= −0.41, p=0.02); similar observations were made in CD14+ monocytes from antiretroviral-treated subjects (r= −0.36, p=0.04). In African-Americans, but not Caucasians, greater GTn repeats were correlated with higher soluble CD14 (sCD14) levels during highly active antiretroviral therapy (HAART) (r= 0.38, p=0.007) as well as higher mean viral load off-therapy (r= 0.24, p=0.04). These data demonstrate that the HO-1 GTn microsatellite polymorphism is associated with higher levels of HO-1 expression and that this pathway may have important effects on the association between inflammation and HIV replication.
PMCID: PMC3330188  PMID: 22048453
Heme oxygenase-1; microsatellite; polymorphism; HIV; soluble CD14; monocytes
4.  Naïve human T cells are activated and proliferate in response to the heme oxygenase-1 (HO-1) inhibitor tin mesoporphyrin 
Heme oxygenase-1 (HO-1) and its catabolic byproducts have potent anti-inflammatory activity in many models of disease. It is not known, however, if HO-1 also plays a role in the homeostatic control of T cell activation and proliferation. We demonstrate here that the HO-1 inhibitor, tin mesoporphyrin (SnMP), induces activation, proliferation, and maturation of naïve CD4+ and CD8+ T cells via interactions with CD14+ monocytes in vitro. This response is dependent upon interactions of T cells with MHC Class I and II on the surface of CD14+ monocytes. Furthermore, CD4+CD25+FoxP3+ regulatory T cells (Tregs) were able to suppress this proliferation, even though their suppressive activity was itself impaired by SnMP. Given the magnitude of the antigen-independent T cell response induced by SnMP, we speculate that HO-1 plays an important role in dampening non-specific T cell activation. Based on these findings, we propose a potential role for HO-1 in the control of naïve T cell homeostatic proliferation.
PMCID: PMC3314532  PMID: 20921523
5.  Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans 
Science (New York, N.y.)  2010;330(6011):1695-1699.
Although the mammalian immune system is generally thought to develop in a linear fashion, findings in avian and murine species argue instead for the developmentally ordered appearance (or “layering”) of unique hematopoietic stem cells (HSC) that give rise to distinct lymphocyte lineages at different stages of development. Here, we provide evidence of an analogous “layered” immune system in humans. Our results suggest that fetal and adult T cells are distinct populations that arise from different populations of HSC present at different stages of development. We also provide evidence that the fetal T cell lineage is biased towards immune tolerance. These observations offer a mechanistic explanation for the tolerogenic properties of the developing fetus and for variable degrees of immune responsiveness at birth.
PMCID: PMC3276679  PMID: 21164017
6.  Increased Circulating Interleukin-7 Levels in HIV-1–Infected Women 
Sex-based differences in CD4 T-cell (CD4) counts are well recognized, but the basis for these differences has not been identified. Conceivably, homeostatic factors may play a role in this process by regulating T-cell maintenance and repletion. Interleukin (IL)-7 is essential for normal T-cell production and homeostasis. We hypothesized that differences in IL-7 might contribute to sex-based differences in CD4 counts. Circulating IL-7 levels were analyzed in 299 HIV-1–infected women and men. Regression analysis estimated that IL-7 levels were 40% higher in women than in men (P = 0.0032) after controlling for CD4 count, age, and race. Given the important role of IL-7 in T-cell development and homeostasis, these findings suggest that higher IL-7 levels may contribute to higher CD4 counts in women.
PMCID: PMC3119025  PMID: 16284535
interleukin-7; sexual dimorphism; CD4-positive T cells; cytokines; sex differences
7.  Maternal Alloantigens Promote the Development of Tolerogenic Fetal Regulatory T Cells in Utero 
Science (New York, N.Y.)  2008;322(5907):1562-1565.
As the immune system develops, T cells are selected or regulated to become tolerant of self antigens and reactive against foreign antigens. In mice, the induction of such tolerance is thought to be attributable to the deletion of self-reactive cells. Here, we show that the human fetal immune system takes advantage of an additional mechanism: the generation of regulatory T cells (Tregs) that suppress fetal immune responses. We find that substantial numbers of maternal cells cross the placenta to reside in fetal lymph nodes, inducing the development of CD4+CD25highFoxP3+ Tregs that suppress fetal antimaternal immunity and persist at least until early adulthood. These findings reveal a form of antigen-specific tolerance in humans, induced in utero and probably active in regulating immune responses after birth.
PMCID: PMC2648820  PMID: 19056990

Results 1-7 (7)