Increased Membrane Cholesterol in Lymphocytes Diverts T-Cells toward an Inflammatory Response

Cell signaling for T-cell growth, differentiation, and apoptosis is initiated in the cholesterol-rich microdomains of the plasma membrane known as lipid rafts. Herein, we investigated whether enrichment of membrane cholesterol in lipid rafts affects antigen-specific CD4 T-helper cell functions. Enrichment of membrane cholesterol by 40–50% following squalene administration in mice was paralleled by an increased number of resting CD4 T helper cells in periphery. We also observed sensitization of the Th1 differentiation machinery through co-localization of IL-2Rα, IL-4Rα, and IL-12Rβ2 subunits with GM1 positive lipid rafts, and increased STAT-4 and STAT-5 phosphorylation following membrane cholesterol enrichment. Antigen stimulation or CD3/CD28 polyclonal stimulation of membrane cholesterol-enriched, resting CD4 T-cells followed a path of Th1 differentiation, which was more vigorous in the presence of increased IL-12 secretion by APCs enriched in membrane cholesterol. Enrichment of membrane cholesterol in antigen-specific, autoimmune Th1 cells fostered their organ-specific reactivity, as confirmed in an autoimmune mouse model for diabetes. However, membrane cholesterol enrichment in CD4+ Foxp3+ T-reg cells did not alter their suppressogenic function. These findings revealed a differential regulatory effect of membrane cholesterol on the function of CD4 T-cell subsets. This first suggests that membrane cholesterol could be a new therapeutic target to modulate the immune functions, and second that increased membrane cholesterol in various physiopathological conditions may bias the immune system toward an inflammatory Th1 type response

Double Negative (CD3+4−8−) TCRαβ Splenic Cells from Young NOD Mice Provide Long-Lasting Protection against Type 1 Diabetes

-reactive T-cells. Herein, we analyzed the function and phenotype of DNCD3 splenic cells in young NOD mice predisposed to several autoimmune disorders among which, the human-like autoimmune diabetes. with a predominant Vβ13 gene usage.T-regulatory cells. DNCD3 splenic cells could be potentially manipulated towards the development of autologous cell therapies in autoimmune diabetes

Immunogenicity of a contiguous T-B synthetic epitope of the A/PR/8/34 influenza virus.

A contiguously linked T-B synthetic viral epitope (110HA120-150HA159,T-B) was investigated for its potency in inducing humoral and cellular immune responses in vivo. The T-cell epitope 110HA120 corresponds to the site 1 hemagglutinin (HA) of the A/PR/8/34 (PR8) influenza virus and is recognized by CD4 T cells in association with I-Ed class II major histocompatibility complex molecules. The 150HA159 represents a major B-cell epitope of the HA protein. T-B dipeptide emulsified in Freund's complete adjuvant was able to induce strong antiviral antibody titers and a high frequency of specific T-cell precursors after a single inoculation in BALB/c mice. In contrast, immunization under identical conditions with equimolar mixtures of T and B peptides did not elicit antibody titers or a cellular immune response. As indicated by the isotypes of antiviral antibodies, the T-B dipeptide preferentially induced a Th1-like immune response. Challenge with T-B dipeptide, but not with T or B peptide alone, stimulated peptide-specific T memory cells in mice previously primed with PR8 virus or with T-B dipeptide. As a consequence, 71 and 57% of these mice, respectively, survived infection with two 100% lethal doses of PR8 virus. Our results suggest that, inasmuch as contiguity between T- and B-cell epitopes provides enough signaling capacity to trigger the mechanisms of T-B-cell cooperation in vivo, a T-B contiguous epitope may well represent a minimal built-in subunit vaccine. Aside from their potential bioavailability, the T-B contiguous epitopes may also represent attractive tools for investigating the molecular mechanisms of T-B-cell cooperation responsible for antiviral protection