Striking a balance: how the gut microbiome shapes the fate of intestinal CD4+ T cells

The induction of immune tolerance, a state of immunologic hyporesponsiveness to an antigen, is essential to prevent the destructive potential of the immune system in response to harmless or beneficial agents. Early efforts to understand tolerance focused on model stimuli, self-antigens, transplanted organs, and the growing fetus. Through co-evolution, the microbiome and the host immune system have developed strategies that promote immunological tolerance to the microbiome. This dialogue ensures the maintenance of mutualistic interactions that provide a stable habitat for the microbiome which in turn confers numerous physiological benefits to the host. Despite the gut microbiome being a potent inducer of immune tolerance, the mechanisms through which specific members shaped immune function remained largely ignored for decades. The growing appreciation for the immunomodulatory capacity of the microbiome has led to a massive expansion of efforts to define how the balance between tolerance and inflammation is induced and maintained at mucosal sites like the intestine. While the ensuing research uncovered myriad fundamental insights into the concerted host and microbial functions promoting host-microbiome mutualism, inducing tolerance to clinically relevant antigens remains a major challenge in the development of tolerogenic therapies. Here, we trace the interaction between intestinal CD4+ T cells and the microbiome, from antigen uptake through to the development of a polarized collection of CD4+ T cells, whose functions are essential for immunological tolerance, and highlight the knowledge gaps that limit efforts to leverage these interactions for clinical benefit.