Sunil K. Joshi

Conditional Ablation of MHC-II Suggests an Indirect Role for MHC-II in Regulatory CD4 T Cell Maintenance

Although the importance of MHC class II (MHC-II) in acute homeostatic proliferation of regulatory T (Treg) cells has been established, we considered here the maintenance and state of Treg cells in mice that are almost completely devoid of MHC-II in their periphery but still make their own CD4 T cells and Treg cells. The latter was accomplished by conditional deletion of a loxP-flanked MHC-II β-chain allele using a TIE2Cre transgene, which causes a very high degree of deletion in hemopoietic/endothelial progenitor cells but without deletion among thymic epithelial cells. Such conditional MHC-II-deficient mice possess their own relatively stable levels of CD4+CD25+ cells, with a normal fraction of Foxp3+ Treg cells therein, but at a level ∼2-fold lower than in control mice. Thus, both Foxp3low/− CD4+CD25+ cells, said to be a major source of IL-2, and IL-2-dependent Foxp3+ Treg cells are reduced in number. Furthermore, CD25 expression is marginally reduced among Foxp3+ Treg cells in conditional MHC-II-deficient mice, indicative of a lack of MHC-II-dependent TCR stimulation and/or IL-2 availability, and IL-2 administration in vivo caused greatly increased cell division among adoptively transferred Treg cells. This is not to say that IL-2 can cause Treg cell division in the complete absence of MHC-II as small numbers of MHC-II-bearing cells do remain in conditional MHC-II-deficient mice. Rather, this suggests only that IL-2 was limiting. Thus, our findings lend support to the proposal that Treg cell homeostasis depends on a delicate balance with a population of self-reactive IL-2-producing CD4+CD25+ cells which are themselves at least in part MHC-II-dependent.

Is HDL function as important as HDL quantity in the coronary artery disease risk assessment

Over the past several decades, it has been clearly established that higher plasma concentrations of high-density lipoprotein (HDL) are related to lower risk of coronary artery disease (CAD). According to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines, thexa0HDL level of <40 mg/dL is considered low and is one of the CAD risk predictors. However, in the last decade, several studies have indicated the importance of the quality of HDL as another potential measure for CAD risk assessment. The loss of normal biological function of HDL particles as a result of multifactorial actions of chronic inflammation and acute phase responses has suggested a new potential pathway in the pathophysiology of atherosclerosis. The concept of dysfunctional HDL or proinflammatory HDL, which exhibits chameleon-like properties of converting a positive force protecting arteries to a negative one, enhancing atherogenesis is now under active investigation. Measurements of this dysfunctional quality of HDL in cell-based or cell-free assays by analyzing anti-inflammatory functions may link these changes to in vivo assessments of vascular disease. This review provides details on functional and dysfunctional HDL and summarizes recent studies into dysfunctional HDL and its potential links to CAD.

The autoimmune regulator (Aire) controls iNKT cell development and maturation.

The mechanism underlying the autoimmune polyglandular syndrome type-1 (APS1) has been attributed to defective T-cell negative selection resulting from reduced expression and presentation of autoantigens in thymic medullary epithelial cells (MECs). It has also been postulated that Aire is involved in development of regulatory T cells, although supporting evidence is lacking. Here we show that expression of Aire in MECs is required for development of iNKT cells, suggesting a role for iNKT cells in APS1. NOTE: We are retracting this report as it contains several errors, including duplications and manipulations of some flow cytometry plots in Figure 1a and in Supplementary Figure 2 online, incorrect juxtaposition of data in Figure 1g (spleen) that in fact derive from different experiments, and inaccurate reporting of the absolute number of iNKT cells and s.d. values, even though the statistical significance remains unchanged. Although original data exist for each figure that largely support the conclusions drawn, we believe that the number of figures affected means that the appropriate response is to retract this paper.