Understanding and overcoming the barriers to T cell-mediated immunity against tuberculosis

Abstract

Despite the overwhelming success of immunization in reducing, and even eliminating, the global threats posed by a wide spectrum of infectious diseases, attempts to do the same for tuberculosis (TB) have failed to date. While most effective vaccines act by eliciting neutralizing antibodies, T cells are the primary mediators of adaptive immunity against TB. Unfortunately, the onset of the T cell response after aerosol infection with Mycobacterium tuberculosis (Mtb), the bacterium that causes TB, is exceedingly slow, and systemically administered vaccines only modestly accelerate the recruitment of effector T cells to the lungs. This delay seems to be orchestrated by Mtb itself to prolong the period of unrestricted bacterial replication in the lung that characterizes the innate phase of the response. When T cells finally arrive at the site of infection, multiple layers of regulation have been established that limit the ability of T cells to control or eradicate Mtb. From this understanding, emerges a strategy for achieving immunity. Lung resident memory T cells may recognize Mtb-infected cells shortly after infection and confer protection before regulatory networks are allowed to develop. Early studies using vaccines that elicit lung resident T cells by targeting the lung mucosa have been promising, but many questions remain. Due to the fundamental nature of these questions, and the need to understand and manipulate the early events in the lung after aerosol infection, only coordinated approaches that utilize tractable animal models to inform human TB vaccine trials will move the field toward its goal.

Keywords: Lung; Regulation; T cell; Tuberculosis; Vaccine.

Figure 1

Three phases of early Mtb infection that contribute to the delayed T cell response. Days 0-8. After aerosol infection Mtb is taken up by alveolar macrophages, in which they reside and replicate for the first 7-8 days. Cell surface lipids restrict recognition of Mtb PAMPs by TLRs, thus limiting macrophage activation and promoting an intracellular environment permissive to Mtb survival and replication. Days 9-14. Eventually, infected macrophages undergo cell death and are taken up by other phagocytic cell types. Neutrophils seem to be the next cell type to harbor Mtb, and their subsequent apoptosis facilitates uptake by migratory DCs and inflammatory monocytes that transport Mtb to the lung dLN. The first component of delayed T cell response during TB, the slow transport of Mtb from the lung to the lymph node (discussed in Section 2.2.1), is depicted in these first two panels. Days 15-21. T cell priming is initiated in the lung dLN, but the inflammatory milieu of Mtb infection promotes expansion of a highly suppressive population of Mtb-specific Tregs. These pathogen-specific Tregs restrict the priming and proliferation of effector T cells, thus delaying their arrival in the lung. This second component of the delayed T cell response during TB is discussed in Section 2.2.2. By the time effector T cells reach the site of infection they encounter immunosuppressive soluble factors, regulatory cell types, and a high bacterial burden that each restrict their functional and protective capacity. A central tenet of this review is that vaccine-induced T cells resident in the lung could potentially mediate superior protection if they were localized to recognize infected alveolar macrophages in the first week of infection.

Figure 2

Schematic showing an approach to vaccine-related TB research that coordinates efforts in animals and humans. Animal studies should be driven by questions arising from human TB and generate hypotheses that inform the direction and design of subsequent human studies. A few examples of such questions and hypotheses are listed, but many others exist. Still more will arise from questions raised in future studies.