The key role of dendritic cells in shaping the T cell response, as studied by Kristen Tarbell at NIH
by Adam Burrack, PhD
Why T cells of the immune system target beta cells in the pancreas for destruction is a complex problem with many partial answers. The answers to this question relate to genetics, the gut microbiome, and diet, among other factors. A more straight-forward question might be, HOW do T cells become activated to specifically destroy beta cell-derived proteins. This, also, is a more complex answer than one might expect, and is the topic of this morning’s post. Read on….
Kristen Tarbell’s group at the National Institutes of Health studies dendritic cell biology – in particular the key function of dendritic cells in promoting or inhibiting T cell responses. I have touched on the critical role of dendritic cells in shaping the T cell response in previous posts, including describing work by Rachel Friedman at the University of Colorado-Denver.
Dendritic cells “sit” at a key decision point in the creation of an immune response. Depending on local environment – context – of how the dendritic cells “show” a peptide to T cells, one of two main paths is taken. The two types of responses are to protect (producing regulatory T cells) or to attack (producing effector T cells). Dr Tarbell and others have shown there are at least two different ‘categories’ of dendritic cells, which promote either tolerance (to self-proteins, preventing autoimmunity) and those which are more suited to promoting responses by CD8+ T cells (ie, “killer” T cells) against pathogens.
In a previous report Dr Tarbell’s group demonstrated that dendritic cells which normally prevent autoimmunity are less effective in NOD mice, the mouse model of type 1 diabetes. This report supports work by Katie Haskins and David Wagner showing that normal regulation of CD4+ T cells (ie, helper T cells) is perturbed in NOD mice. Taken together, there appear to be defects at multiple stages of T cell activation and regulation leading to type 1 diabetes.
In a 2015 manuscript in the journal Diabetes, Dr. Tarbell and colleagues develop a better understanding of why normal T cell regulation is ineffective in NOD mice and attempt to develop methods to improve T cell regulation through dendritic cells. This approach has the potential to be very efficient: a single dendritic cell can interact with dozens, perhaps hundreds, of individual T cells. As such, dendritic cells are a true rate-limiting factor in T cell responses.
In this study, Dr. Tarbell showed that tolerance-promoting dendritic cells, if they maintained a tolerance-promoting phenotype, can delay diabetes development in NOD mice. This paper also demonstrates that tolerance-promoting dendritic cells are exceptionally effective in NOD mice, promoting diabetes. Third, tolerance-promoting dendritic cells express higher levels of “co-stimulatory” molecules than dendritic cells from mice which are not prone to autoimmunity: again tipping the scales toward developing autoimmunity. Finally, the key result of this paper was the discovery of a transcription factor – transcription factors control which proteins are made in cells – which is produced in tolerance-promoting dendritic cells. Long story short, this transcription factor shows promise as a ‘master regulatory’ of sorts for dampening down inappropriate immune responses.
Much work remains to be conducted in this area. Suffice to say, basic researchers are developing an ever-improving understanding of the genetic control of immune responses. Long-term, we hope this understanding can be utilized to develop therapeutics to delay – or better to prevent – inappropriate immune responses including autoimmunity.