CD8+CD57+ T lymphocytes, present at low levels in the peripheral blood of healthy individuals expand during HIV infection and remain elevated during chronic infection. Their role in the immune response remains unclear. We performed a large-scale gene array analysis (3158 genes) to characterize them and, interestingly, found no distinction in the transcriptional profiles of CD8+CD57+ T lymphocytes from HIV-infected and uninfected subjects. In both groups, these cells showed specificity for multiple Ags and produced large amounts of IFN-γ and TNF-α. The transcriptional profiles of CD8+CD57+ and CD8+CD57− cells, however, differed substantially. We propose that CD8+CD57+ cells were Ag-driven effector cells with very high cytotoxic effector potential including perforin, granzymes, and granulysin, regardless of HIV status. At both the messenger and protein levels, they expressed more adhesion molecules and fewer chemokine receptors (CCR7 and CXCR4) than CD8+CD57− cells but expressed preferentially CX3CR1. The lower expression level of genes involved in cell cycle regulation showed limited proliferation capacities of CD8+CD57+ even in response to TCR and IL-2, IL-7, and IL-15 stimulation. CD8+CD57+ T cells from both HIV and uninfected subjects maintain effective cytotoxic potentials but are destined to migrate to nonlymphoid tissues without further cycling.

Objective-CC chemokine receptor CCR5 is expressed by atheroma-associated cells and could mediate leukocyte attraction into developing lesions. We examined the role of bone marrow-derived CCR5 in the development of atherosclerotic lesions after 8, 12, or 35 weeks of high-fat diet. Methods and Results-Low-density lipoprotein-receptor (LDLr)-deficient mice were lethally irradiated and transplanted with CCR5 ϩ/ϩ or CCR5 Ϫ/Ϫ bone marrow. After 8 weeks of fat diet, CCR5 deficiency in leukocytes led to 30% decrease of macrophage accumulation within the fatty streak (PϽ0.05), with no change in lesion size. After 12 weeks of fat diet, CCR5 deficiency also resulted in 30% decrease of plaque-macrophage accumulation (PϽ0.005), associated with 16% reduction in lesion size in the aortic sinus (Pϭ0.13), despite a significant increase in total cholesterol levels (Pϭ0.03). Lesions with CCR5 deficiency showed 52% reduction in matrix metalloproteinase (MMP)-9 expression (Pϭ0.02) and 2-fold increase in collagen accumulation (PϽ0.0001). These changes were associated with a significant increase of interleukin (IL)-10 mRNA expression in spleens of CCR5 Ϫ/Ϫ mice compared with CCR5 ϩ/ϩ controls. In addition, we found enhanced IL-10 production by CCR5-deficient peritoneal macrophages and decreased tumor necrosis factor (TNF)-␣ production by CCR5 Ϫ/Ϫ T cells in comparison with CCR5 ϩ/ϩ controls. CCR5 Ϫ/Ϫ and CCR5 ϩ/ϩ reconstituted animals showed no differences in plaque size or composition after 35 weeks of high-fat diet despite the persistent absence of CCR5 in plaques of mice reconstituted with CCR5 Ϫ/Ϫ bone marrow. Key Words: atherosclerosis Ⅲ chemokines Ⅲ cytokines Ⅲ inflammation A therosclerosis is a chronic inflammatory disease of the arterial wall, characterized by the accumulation of leukocytes, especially macrophages and T cells. [1][2][3][4] These cells first interact with the endothelial layer and then migrate to the subendothelial space where monocytes become lipidloaded macrophages and interact with T cells and vascular cells. These mechanisms rely on the expression of adhesion and chemotactic molecules that are produced within the vascular wall and facilitate cell migration while amplifying local immune responses. [5][6][7] The importance of chemokines in atherosclerosis was demonstrated by gene disruption experiments. As a result, various chemokines and chemokine receptors have already been reported to be expressed in atherosclerotic arteries and to play key roles in the development of atherosclerosis. 8 -14 The chemokine receptor CCR5 is expressed on cells that contribute to disease progression (macrophages, T cells, and smooth muscle cells), and has several ligands (RANTES, MIP-1␣, MIP-1␤) detected in plaques. [15][16][17][18][19] In vitro studies revealed the role of CCR5 in mediating leukocyte attraction, 20 a step critical to atherosclerosis initiation, and the ability of its ligands to induce tissue factor 17 or MMP expression, 21 which contribute to plaque complications and thrombotic processes. Moreover, genetic sc...

CCR6, a homeostatic chemokine receptor, is shown here to characterize subsets of both central and effector memory T cells that secrete high levels of IL-2 and TNF-α in response to polyclonal and antigen-specific stimulation. CCR6+ T lymphocytes disappeared dramatically from the peripheral blood of HIV-infected patients as HIV disease progressed. The capacity of CD4+CCR6+ to secrete multiple cytokines remained intact among HIV-infected long-term nonprogressors but was partially lost from subjects with standard disease progression. CCR6+ T lymphocytes, regardless of their CCR7 expression, accumulated in the spleen of HIV-infected patients, where they died by apoptosis. Assessment of CCR6 expression allowed us to describe novel memory T-cell subpopulations capable of high cytokine production and provided evidence of a pathologic CCR6-dependent pathway of memory T-cell homing that may participate in the loss of memory response against infections.