Abstract
T-cell mediated immune responses should be regulated to avoid the development of autoimmune or chronic inflammatory diseases. Several mechanisms have been described to regulate this process, namely death of overactivated T cells by cytokine deprivation, suppression by T regulatory cells (Treg), induction of expression of immune checkpoint molecules such as CTLA-4 and PD-1, or activation-induced cell death (AICD). In addition, activated T cells release membrane microvesicles called exosomes during these regulatory processes. In this review, we revise the role of exosome secretion in the different pathways of immune regulation described to date and its importance in the prevention or development of autoimmune disease. The expression of membrane-bound death ligands on the surface of exosomes during AICD or the more recently described transfer of miRNA or even DNA inside T-cell exosomes is a molecular mechanism that will be analyzed.
Highlights
T-cell mediated immune responses should be regulated to avoid the development of autoimmune or chronic inflammatory diseases
Immune regulation by CTLA-4 is important since CTLA-4 knockout mice develop fatal lymphoproliferative disorders [11] and mutations in the CTLA-4 gene have been associated in humans with an increased risk of autoimmune disease [12,13]
Another important checkpoint molecule is PD-1 [14], which is expressed on the surface of T cells upon activation, and that, by binding to its ligands PD-L1 and PD-L2, activate tyrosine phosphatase activities promoting the turning off of tyrosine kinase-mediated activating signals [15]
Summary
The maintenance of immune homeostasis is dependent on immune tolerance towards self-tissues and is a complex process, necessary to avoid autoimmunity. Immune regulation by CTLA-4 is important since CTLA-4 knockout mice develop fatal lymphoproliferative disorders [11] and mutations in the CTLA-4 gene have been associated in humans with an increased risk of autoimmune disease [12,13] Another important checkpoint molecule is PD-1 [14], which is expressed on the surface of T cells upon activation, and that, by binding to its ligands PD-L1 and PD-L2, activate tyrosine phosphatase activities promoting the turning off of tyrosine kinase-mediated activating signals [15]. This mechanism is important to down-modulate inflammation in peripheral tissues in a physiological manner [16]. No autoimmune disease is known to be associated with TRAIL mutations, TRAIL-knockout mice are more sensitive to the induction of experimental autoimmune diseases [29]
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