The role of cytokines in the initiation, expansion, and control of cellular immunity to tuberculosis

Abstract

Tuberculosis (TB) results from an interaction between a potent immune response and a chronically persistent pathogen. The ability of Mycobacterium tuberculosis (Mtb) to induce a strong immune response while being able to resist the ability of the host to clear bacteria provides an excellent tool with which to investigate the role of specific cytokine pathways on the induction, expansion, and control of the effector T-cell response. In this review, the role of interleukin-12p40 (IL-12p40), IL-12p70, IL-23, and IL-27 in the immune response to Mtb are described. We show that IL-12(p40)(2) acts to mediate the activation of dendritic cells to become responsive to homeostatic chemokines. We also show that IL-12p70 is required for the optimal interferon-gamma (IFN-gamma) T-cell response, which is required for control of Mtb growth. IL-23 can induce IFN-gamma responses in the lung if IL-12 is not present, but its major role is in supporting the IL-17 response within the lung. Neither IL-23 nor IL-17 is required for early control of Mtb in the lung. IL-23 and IL-17, however, can be instrumental in vaccine-induced protection. Finally, IL-27 limits protective immunity in the lung, but it is also required for long-term survival. These cytokines are therefore key players in the immune response to TB.

Fig. 1. Low-dose aerosol infection with Mtb results in growth of bacteria and slow induction of immunity in the lung

(A) Bacterial colonization of the lung occurs upon infection with approximately 75 bacterial colony-forming units within aerosol particles of 3–5 μm diameter. After 3 days, bacteria begin to grow logarithmically until day 20, whereupon their growth is slowed. (B) Ex vivo stimulation of cells with peptide containing an IAb-restricted epitope demonstrates that the accumulation of IFN-γ-producing cells within the lung is slow but correlates with cessation of bacterial growth. (C) The cessation of bacterial growth and arrival of 10⁴ IFN-γ-producing T cells also correlates in time with the upregulation of class II MHC on CD11c⁺ cells within the lung.

Fig. 2. IL-12-related cytokines and their receptors

Dimeric cytokines utilizing the IL-12p40, IL-12p35, IL-23p19, EBI3, and p28 subunits share subunits and receptor components. All subunits are induced during Mtb infection in mice, and most play a role in the initiation, expansion, and regulation of the cellular response to Mtb.

Fig. 3. Cytokines play an intrinsic role in the cellular response to Mtb infection in the lung

(A) Migration of Mtb-infected DCs can be influenced by IL-12p40 and the development of effector subpopulations of antigen-specific cells depends upon IL-12p70, IL-23, and IL-27. The Th17 population is regulated by IL-12p35 possibly as a result of IL-35. Effector T-cell populations are required for the generation of the mononuclear granuloma and the control of bacterial growth. (B) Following subunit vaccination, a population of IL-17-producing IL-23-dependent antigen-specific memory cells can populate the lung. These cells respond to infection and accumulate in the lung. A circulating population of IFN-γ-producing IL-12p70-requiring antigen-specific memory cells sees antigen (likely in the lymph node), expands, and is recruited to the lung as a result of a chemokine response that is dependent upon the IL-17-producing memory population. The accelerated accumulation of cells in the lung results in earlier cessation of bacterial growth and a reduced bacterial burden. (C) Failure of the immune response to eliminate bacteria results in chronic infection and stimulation of antigen-specific immune responses. Repeated antigen exposure results in detrimental changes, specifically increase in size of the lesion and an increase in granulocyte accumulation; this effect may be the result of an altered balance in the subsets of effector T cells. The maintenance of the mononuclear granuloma is dependent upon a variety of factors, the loss of anyone of which can result in development of damaging inflammation and resurgence of bacterial growth.