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Review
. 2012 Oct 4:1:6.
doi: 10.1186/2046-2395-1-6. eCollection 2012.

Aging, immunosenescence and membrane rafts: the lipid connection

Tamas Fulop  1 , Aurélie Le Page  2 , Hugo Garneau  2 , Naheed Azimi  2 , Sarra Baehl  2 , Gilles Dupuis  3 , Graham Pawelec  4 , Anis Larbi  5
Affiliations
Review

Aging, immunosenescence and membrane rafts: the lipid connection

Tamas Fulop et al. Longev Healthspan. .

Abstract

The decreased efficiency of immune responses in older people is partly a consequence of alterations in T lymphocyte functions caused by modifications in the early events of signal transduction. Several alterations in the signaling pathways of T lymphocytes have been described in older humans and animals. A unifying cause could be modifications in the physicochemical properties of the plasma membrane resulting from changes in its lipid composition and the distribution and function of lipid rafts (LR). The latter serve to assemble the initial components of the signaling cascade. Accumulating data suggest that the function of plasma membrane LR is altered with aging; we hypothesize that this would significantly contribute to immune dysregulation. The role of aging and cholesterol in LR functions in T lymphocytes is reviewed and discussed here.

Keywords: Cholesterol; Immune synapse; Immunosenescence; Lipid rafts; Signal transduction; T cells.

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Figures

Figure 1
Figure 1
Signal 1 and 2 during T cell activation. Upon antigen presentation by professional antigen presenting cells (APC), multiple stimulatory molecules control full activation of T cells. Signal 1 is delivered by CD4/CD8 and T cell receptor (TCR)/major histocompatibility (MHC) interaction while signal 2 is delivered by CD28/B7 interaction (or other co-stimulator-receptor pairs) The two signals together are required to induce IL-2 production which will have autocrine and paracrine effects.
Figure 2
Figure 2
Lck is a central node in the T cell receptor signaling pathway. (A) Following T cell receptor (TCR)/CD3 complex ligation, Lck phosphorylation sites (inhibitory Tyr505 and activatory Tyr394) regulate Lck activity. The phosphorylation of immunotyrosine-based activating motifs (ITAMs) by Lck induces recruitment of other kinases and leads to T cell activation. Phosphorylation of Lck is regulated positively by CD45 and negatively by C-terminal Src kinase (Csk), itself regulated by phosphoprotein associated with GEMs (PAG), and Src homology 2 domain-containing protein tyrosine-phosphatase 1 (SHP-1). The regulation of phosphatases such as SHP-1 is strongly influenced by oxidative stress (reactive oxygen species) and the Nrf2 pathway. (B) Nrf2 quantification in resting and activated (anti-CD3/CD28) T cell cytoplasm in young versus older individuals is shown (a representative blot is shown). In addition, there are other regulatory mechanisms that function rapidly as negative feedback loops from the TCR signalosome itself [19]. One of these involves phosphatases, especially SHP-1 [35]. Reduction of SHP-1 activity upon stimulation lowers the threshold for TCR activation. It seems that under weak stimulation activated Lck associates with and phosphorylates SHP-1, the activity of which then becomes reduced, but not sufficiently to allow full signaling to occur. Thus, under strong stimulation, Lck activity would increase or become sufficient when SHP-1 activity is reduced very early in the signaling cascade. In turn, when the signal weakens, SHP-1 activity increases and consequently downregulates Lck activity [36]. Many other negative feedback mechanisms are in operation during the early and late phases of TCR signaling [19].
Figure 3
Figure 3
Impact of lipid factors on T cell function. Proliferation was measured after T cell activation with CD3/CD28 antibodies. Peripheral blood mononuclear cells (PBMC) from young and older people were treated with 5 mM methyl β-cyclodextrin (MBCD) for 30 minutes to extract membrane cholesterol prior to culturing. *P <0.01.
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