Lipid rafts in T cell signalling and disease

Abstract

Lipid rafts is a blanket term used to describe distinct areas in the plasma membrane rich in certain lipids and proteins and which are thought to perform diverse functions. A large number of studies report on lipid rafts having a key role in receptor signalling and activation of lymphocytes. In T cells, lipid raft involvement was demonstrated in the early steps during T cell receptor (TCR) stimulation. Interestingly, recent evidence has shown that signalling in these domains differs in T cells isolated from patients with autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Here, we discuss these findings and explore the potential of lipid rafts as targets for the development of a new class of agents to downmodulate immune responses and for the treatment of autoimmune diseases.

Fig. 1

Increased levels of cholesterol and GM1 in the plasma membrane of T cells from patients with SLE and activated normal T cells. (A) Purified T cells from SLE patients and healthy controls were labelled with the cholesterol chelator filipin and analysed by flow cytometry. The results shown are the cumulative data collected from five lupus patients and five healthy volunteers. (B) SLE and normal T cells were stained with Alexa-fluor 594-conjugated cholera toxin B subunit (CTB-Alexa 594) and analysed by confocal microscopy. The images shown are adjusted to the same output intensity and are representative of samples generated from two healthy donors and two SLE patients. Bar = 10 μm. (C) Peripheral blood T cells from healthy donors were activated in vitro with a combination of anti-CD3/anti-CD28 antibodies and stained with CTB-Alexa 594 or filipin to assess the levels of GM1 and cholesterol, respectively.

Fig. 2

Differential association of signalling molecules to lipid raft domains in SLE may contribute to a breakdown in peripheral T cell tolerance. Higher synthesis of cholesterol and of other lipids could result in larger or more stable lipid raft domains. These changes in the plasma membrane could be the reason for the increased co-localization of CD45 phosphatase with lipid rafts and the higher Lck activity seen in SLE T cells. Enhanced protein–protein interactions and changes in enzymatic activity could lower the threshold for TCR activation.