Cytokines and Chemokines in Mycobacterium tuberculosis Infection

Abstract

Chemokines and cytokines are critical for initiating and coordinating the organized and sequential recruitment and activation of cells into Mycobacterium tuberculosis-infected lungs. Correct mononuclear cellular recruitment and localization are essential to ensure control of bacterial growth without the development of diffuse and damaging granulocytic inflammation. An important block to our understanding of TB pathogenesis lies in dissecting the critical aspects of the cytokine/chemokine interplay in light of the conditional role these molecules play throughout infection and disease development. Much of the data highlighted in this review appears at first glance to be contradictory, but it is the balance between the cytokines and chemokines that is critical, and the "goldilocks" (not too much and not too little) phenomenon is paramount in any discussion of the role of these molecules in TB. Determination of how the key chemokines/cytokines and their receptors are balanced and how the loss of that balance can promote disease is vital to understanding TB pathogenesis and to identifying novel therapies for effective eradication of this disease.

Figure 1. The role of chemokines and cytokines in the innate response to Mtb infection

Upon early infection of the lower airways, Mtb encounters alveolar macrophages and lung epithelial cells. Alveolar macrophages are a major source of proinflammatory cytokines (TNFα), although stromal cells can produce cytokines and chemokines which will also modulate immune responses. During early infection, dendritic cell trafficking from the lungs to the lymph node via CCR7 results in primed naïve T cells and initiation of adaptive immune responses. Replicating bacteria generate a fulminant reaction which results in the mobilization and recruitment of both neutrophils and monocytes from the bone marrow via the induction of proinflammatory cytokines and chemokines. Regulation of cellular recruitment occurs via coordinated cytokine and chemokine induction. While initial recruitment of monocytes requires type I IFN, over-expression of this cytokine results in high levels of CCR2 expressing monocytes with limited ability to control bacterial growth. Type II IFN (IFNγ) regulates the recruitment of neutrophils which is promoted by IL-17. CXCL5 and CXCR2 mediate the recruitment of damaging neutrophils.

Figure 2. The role of chemokines and cytokines in the adaptive response to Mtb infection

Following Mtb infection of the lung, migratory cells take the bacteria to the draining lymph node likely using both cytokine (IL-12p40) and chemokine (CCR2, CCR7) pathways. Antigen is then transferred to antigen presenting cells which stimulate naïve T cells via MHC class I and class II. Antigen presenting cells make cytokines and chemokines to potentiate T cell proliferation and polarization. Activated T cells migrate from the draining lymph node through the vasculature to the inflamed site. Some T cells remain in the vasculature (CX3CR3⁺) while others migrate into the parenchyma (CXCR3⁺CCR6⁺). Expression of CXCR5 on antigen-specific T cells allows them to respond to IL-23- and IL-17-dependent CXCL13 and locate effectively within the granuloma, where they activate Mtb infected macrophages. T cells express a variety of cytokines in the lung including IFNγ, TNFα, IL-17, and IL-10 which have both protective and negative effects depending upon the context.