Polyunsaturated fatty acids, membrane organization, T cells, and antigen presentation

Dietary supplementation with polyunsaturated fatty acids (PUFAs), especially those of the n-3 class, has immunosuppressive effects on both innate and adaptive immunity through various mechanisms. In this review, we focus on the PUFA modulation of membrane architecture and its consequent effects on both T cell responses and antigen presentation. We first use data from in vitro and in vivo experiments to make the case that the immunosuppressive effects of PUFAs begin with membrane incorporation and modulation of lipid-protein lateral organization. This in turn inhibits downstream signaling mediated by T cell receptors and suppresses T cell activation and proliferation. Next, we review evidence for PUFA-mediated alteration of major histocompatibility complex class I and II surface expression and antigen presentation. We propose that PUFAs influence the expression of major histocompatibility complex by altering its conformation, orientation, lateral organization, and trafficking, with consequences for recognition by effector T cells. Finally, we present data from model membrane studies to explain the physical principles that make PUFA acyl chains unique in modifying membrane lateral organization and protein function. An important concept to emerge from these studies is that PUFA acyl chains and cholesterol molecules are sterically incompatible. By applying this concept to the T cell activation and signaling model, mechanisms emerge by which PUFAs can modulate membrane lipid-protein lateral organization. Our data-based models show that membrane modification of both effectors and targets is an important, often overlooked, mechanism of immunomodulation by PUFAs.