A fine balance exists between immunity to pathogens and tolerance to our own cells. We usually think of a robust immune response as beneficial, keeping us healthy from foreign invaders. However, when a response is too robust, ailments like autoimmune diseases can occur. Over the past 2 decades a large amount of research has uncovered a previously underappreciated set of immune cells: T regulatory cells (Tregs). These cells can actually suppress the immune system, and it remains unclear as to how Tregs maintain this balance during some infections, such as West Nile virus. West Nile virus is a single stranded RNA virus that is transmitted to humans via mosquito bites, and subsequent to infection the host produces an antiviral immune response to curb the progression to debilitating central nervous system (CNS) disease such as encephalitis.
A useful experimental tool for analyzing the effect Tregs have on antiviral immunity is the Foxp3DTR mouse. Tregs in this recombinant mouse line express the diphtheria toxin receptor and when the mice are treated with the toxin, Tregs are ablated. This murine model allows one to deplete specifically the Treg cell population and then ask the question: what role(s) do Tregs have on [insert your favorite question]? The authors, including VIDD Staff Scientist Dr. Jessica Graham and Assistant Member Dr. Jennifer Lund, investigated the role Tregs play in the generation of effector and memory T-cell responses in the spleen and CNS after West Nile infection.
Adapted from Graham, et al.
They first infected normal and Treg depleted mice with West Nile virus, harvested the spleens and brains, and then analyzed the characteristics and population size of effector T cells in both tissue microenvironments. In the Treg depleted mice they observed an increase in the production of the antiviral cytokine IFNγ by CD4 and CD8 T cells in both the spleen and CNS. The population of short lived CD8 T cells increased in the spleens of mice lacking Tregs, whereas at 60 days post infection Tregs were necessary for the development of long lasting CD8 memory T cells in the CNS (Figure, left panel). Resident memory T cells rely, in part, on the cytokine TGF-β for retention in the CNS. TGF-β levels were drastically decreased in the Treg deficient mice, suggesting a mechanism in which Tregs secrete TGF-β that subsequently leads to CD8 memory T-cell retention (Figure, right panel). This study accentuates the complexity of the immune system, as Tregs played a role in both dampening the T-cell response to West Nile infection while simultaneously promoting the survival of West Nile virus-specific memory immunity.
Graham JB, Da Costa A, Lund JM. Regulatory T cells shape the resident memory T cell response to virus infection in the tissues. J Immunol. 2014 Jan 15;192(2):683-90.