A study published in the journal Immunity reveals a new role of TRAIL-expressing NK cells during chronic viral infection that may provide further insights into the link between viruses and autoimmune disease development.
Natural killer (NK) cells, a central player in innate immunity, are usually recruited to sites of cellular transformation or intracellular infection that mediate cytotoxic activities and cytokine secretion. Additional functions of NK cells have been uncovered in recent years that demonstrate their role in immunoregulation.
The NK cells exert immunoregulatory functions in the early stages of the immune responses, but very little is known about the potential activities of NK cells at later times, especially in chronic inflammatory pathologies associated with persistent viral infections.
In settings such as transplantation or the development of autoimmunity, NK cells also limit T cell activation, though the mechanisms have yet to be clearly defined. The role of NK cells in chronic inflammatory situations, especially in nonlymphoid tissues, is also poorly defined.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL, also known as Apo2L and TNFSF10) is a type II transmembrane protein belonging to the tumor necrosis factor (TNF) superfamily. TRAIL)/Apo1L is a death ligand, a cytokine that activates apoptosis through cell surface death receptors. TRAIL is thought to be important in host tumor surveillance and metastasis suppression. TRAIL is expressed on the surface of natural killer (NK) and T cells, macrophages, and dendritic cells.
TRAIL was originally identified on the basis of its homology with TNF and its capacity to induce apoptosis in tumor cells. TRAIL mediates its apoptotic effects via specific death receptors that are typically absent from normal cells and tissues.
TRAIL/Apo2L) induces mostly apoptosis and selective toxicity for cancer cells, but also inhibits autoimmune diseases in a number of animal models, through a variety of mechanisms ranging from inhibiting cytokine and antibody production to suppressing proliferation of autoreactive T cells (Erika Cretney et al., Immunology and Cell Biology, 2006, 84:87).
It is also known that some viral infections may contribute to autoimmune diseases but the mechanisms are poorly understood.
In the Immunity study Iona Schuster and co-workers from the University of Western Australia and the Lions Eye Institute, Nedlands, Australia
define a novel interaction between NK cells and CD4+ T cells during chronic viral infection in vivo. This interaction occurs in a nonlymphoid tissue, specifically involves TRAIL-expressing NK cells, and results in the elimination of activated CD4+ T cells.
The investigators report that a novel TRAIL+ NK cell subset regulates immune responses during chronic viral infection. These NK cells specifically eliminate activated CD4+ T cells in the salivary gland during chronic murine cytomegalovirus infection. These data provide clear evidence for the influence of NK cells on the adaptive immune response to chronic viral infection in a nonlymphoid tissue. Moreover, these results clearly demonstrate a NK cell-dependent, TRAIL-mediated killing of a physiologically important CD4+ T cell population in vivo, which results in limiting antiviral responses to curb the development of autoimmunity.
The authors make a case that in the framework of murine cytomegalovirus-induced autoimmunity, autoreactivity may be ‘constrained’ through the elimination of CD4+ T cells by TRAIL-expressing NK cells. In the absence of this activity, chronic infection was associated with a Sjogren’s-like set of symptoms in the experimental animals that had all the major features of human Sjogren’s syndrome.
The authors also suggest that the “expression of TRAIL by NK cells may serve as a general mechanism by which NK cells limit the persistence of activated cells at sites of inflammation and infection, to encourage the resolution of the response”.
Thus, from one point of view, an effector CD4+ T cell population is critical for control of chronic viral infection, but on the other, a population of NK cells acts to specifically eliminate these T cells, thereby suppressing autoimmunity. Therefore, NK cells are an important homeostatic control that balances the efficacy of adaptive immune responses with the risk of developing autoimmunity.
In conclusion, this work reveals a novel and unexpected capacity of NK cells, a prototypical innate lymphocyte population, in the context of chronic viral infection. Importantly, they highlight novel interplays between NK cells and T cells. On one hand, an effector CD4+ T cell population is crucial for control of chronic viral infection, but on the other, a population of NK cells acts to specifically eliminate these T cells, thereby reducing autoimmunity.
These observations and mechanisms may have important implications for Sjogren’s syndrome or other systemic autoimmune diseases where viral etiopathogenesis might be involved.