Orchestration of pulmonary T cell immunity during Mycobacterium tuberculosis infection: immunity interruptus

Abstract

Despite the introduction almost a century ago of Mycobacterium bovis BCG (BCG), an attenuated form of M. bovis that is used as a vaccine against Mycobacterium tuberculosis, tuberculosis remains a global health threat and kills more than 1.5 million people each year. This is mostly because BCG fails to prevent pulmonary disease--the contagious form of tuberculosis. Although there have been significant advances in understanding how the immune system responds to infection, the qualities that define protective immunity against M. tuberculosis remain poorly characterized. The ability to predict who will maintain control over the infection and who will succumb to clinical disease would revolutionize our approach to surveillance, control, and treatment. Here we review the current understanding of pulmonary T cell responses following M. tuberculosis infection. While infection elicits a strong immune response that contains infection, M. tuberculosis evades eradication. Traditionally, its intracellular lifestyle and alteration of macrophage function are viewed as the dominant mechanisms of evasion. Now we appreciate that chronic inflammation leads to T cell dysfunction. While this may arise as the host balances the goals of bacterial sterilization and avoidance of tissue damage, it is becoming clear that T cell dysfunction impairs host resistance. Defining the mechanisms that lead to T cell dysfunction is crucial as memory T cell responses are likely to be subject to the same subject to the same pressures. Thus, success of T cell based vaccines is predicated on memory T cells avoiding exhaustion while at the same time not promoting overt tissue damage.

Keywords: Cytokine; Exhaustion; Memory; Priming; T cell; Tuberculosis.

Figure 1. Complex interactions between resident and recruited innate leukocytes lead to bacterial dissemination and acquisition of antigen by DC for T cell priming

Multiple cell types are initially infected including macrophages, PMNs and DCs. Both apoptotic and necrotic types of cell death can occur following primary M. tuberculosis infection. Apoptosis is associated with control of infection and can lead to acquisition of antigen by APC by the process of efferocytosis. In contrast, necrosis facilitates dispersal of bacteria and re-infection of other cell types. DC, whether they have acquired antigen via efferocytosis or by infection, traffic to the lung draining LN where they have a vital role in T cell priming.

Figure 2. Up to three signals are required for optimal T cell priming

Classically, priming of naïve CD4+ and CD8+ T cells requires two signals. Signal 1 is from the engagement of the T cell receptor (TCR) by cognate peptide presented in the context of major histocompatibility complex (MHC) molecules on the surface of antigen presenting cells (APC). Signal 2 is provided by the interaction of costimulatory receptors, here CD28, with the appropriate ligand, here B7.1 or B7.2. More recently, the model of CD8+ T cell priming has been expanded to include a third signal. Signal 3 is generated by an inflammatory cytokine, usually IL-12 or type 1 interferons (Type 1 IFN). These cytokines bind receptors on the CD8+ T cell and affect expansion, differentiation, effector functions, and memory formation. Additional abbreviations: IL-12R, IL-12 receptor; IFNAR, interferon alpha/beta receptor.

Figure 3. Migration of M. tuberculosis-specific T cells into the lung

To contain bacterial replication, antigen-specific effector T cells migrate from blood into the infected lung tissue, where they directly interact with MHC/peptide complexes on bacilli-laden macrophages. M. tuberculosis-specific CD4+ T cells that express low levels of KLRG1 and high levels of CXCR3 migrate efficiently into the lung parenchyma where they upregulate PD-1, while CD4+ T cells that express high levels of KLRG1 and CX3CR1 are highly enriched in the lung vasculature.

Figure 4. T cell effector functions that activate macrophages to kill M. tuberculosis

Specific recognition of infected target cells, as indicated by TCR signaling, leads to the expression of several effector function that can activate macrophages to kill intracellular M. tuberculosis. The best characterized for rodent models and people are cytokines including IFNγ, TNF, and GM-CSF. There is also evidence for humans and a number of other species that CTL activity, generally in a perforin-dependent manner, also leads to a reduction of intracellular bacterial growth. Finally, T cells indirectly promote host resistance through their immunoregulatory actions – most relevant here is the production of chemokines that recruit other cells to the infectious focus, promote granuloma formation, and infection containment.

Figure 5. Chronic M. tuberculosis infection leads to functional impairment of T cells

As M. tuberculosis establishes a chronic infection, the composition of T cell population changes and more polyfunctional T cells are lost. T cell exhaustion develops in a step-wise and progressive loss of IFNγ, TNF and IL-2. Both intrinsic T cell factors and extrinsic factors in the microenvironment mold the exhaustion signature. Exhausted T cells express an array of inhibitory receptors such as PD-1, Tim-3, Lag-3 and 2B4 and distinctive patterns of cytokine receptors and transcription factors (Blimp-1), which distinguish them from conventional effector T cells. While inhibitory receptors such as PD-1 may impair bacterial control during chronic M. tuberculosis infection, PD-1 is also prevents CD4+ T cell-driven tissue destruction.