Regulation of Immunity to Tuberculosis

Immunity against Mycobacterium tuberculosis requires a balance between adaptive immune responses to constrain bacterial replication and the prevention of potentially damaging immune activation. Regulatory T (Treg) cells express the transcription factor Foxp3+ and constitute an essential counterbalance of inflammatory Th1 responses and are required to maintain immune homeostasis. The first reports describing the presence of Foxp3-expressing CD4+ Treg cells in tuberculosis (TB) emerged in 2006. Different Treg cell subsets, most likely specialized for different tissues and microenvironments, have been shown to expand in both human TB and animal models of TB. Recently, additional functional roles for Treg cells have been demonstrated during different stages and spectrums of TB disease. Foxp3+ regulatory cells can quickly expand during early infection and impede the onset of cellular immunity and persist during chronic TB infection. Increased frequencies of Treg cells have been associated with a detrimental outcome of active TB, and may be dependent on the M. tuberculosis strain, animal model, local environment, and the stage of infection. Some investigations also suggest that Treg cells are required together with effector T cell responses to obtain reduced pathology and sterilizing immunity. In this review, we will first provide an overview of the regulatory cells and mechanisms that control immune homeostasis. Then, we will review what is known about the phenotype and function of Treg cells from studies in human TB and experimental animal models of TB. We will discuss the potential role of Treg cells in the progression of TB disease and the relevance of this knowledge for future efforts to prevent, modulate, and treat TB.