Dendritic Cell Trafficking and Antigen Presentation in the Human Immune Response toMycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis (Mtb) is an extraordinarily successful human pathogen, one of the major causes of death by infectious disease worldwide. A key issue for the study of tuberculosis is to understand why individuals infected with Mtb experience different clinical outcomes. To better understand the dynamics of Mtb infection and immunity, we coupled nonhuman primate experiments with a mathematical model we previously developed that qualitatively and quantitatively captures important processes of cellular priming and activation. These processes occur between the lung and the nearest draining lymph node where the key cells mediating this process are the dendritic cells (DC). The nonhuman primate experiments consist of bacteria and cell numbers from tissues of 17 adult cynomolgus macaques (Macaca fascicularis) that were infected with Mtb strain Erdman (∼25 CFU/animal via bronchoscope). The main result of this work is that delays in either DC migration to the draining lymph node or T cell trafficking to the site of infection can alter the outcome of Mtb infection, defining progression to primary disease or latent infection and reactivated tuberculosis. Our results also support the idea that the development of a new generation of treatment against Mtb should optimally elicit a fast DC turnover at the site of infection, as well as strong activation of DCs for maximal Ag presentation and production of key cytokines. This will induce the most protective T cell response.

The innate immune response in human tuberculosis

“…They have a multitude of receptors to detect Mtb PAMPs and are highly efficient phagocytes (Henderson et al ., 1997). After uptake of Mtb, DCs in the alveoli mature and present antigens via Major Histocompatibility Complex (MHC) class I and II to T cells in the local draining lymph node (Marino et al ., 2004); thus, DCs are a link between the innate and adaptive immune response. However, the outcome of Mtb and DC interaction is complex and not well understood, likely to be due to variation in host genetics and bacterial virulence factors.…”

Dendritic cell interactions withHistoplasmaandParacoccidioides

“…1 In the lung tissue specifically, DCs are located within the airway epithelium, lung parenchyma, and submucosa; within alveolar septal walls and on the alveolar surface. 13,14 Their presence in pulmonary tissue is particularly important in mediation of the immune response to airborne pathogens such as, A. fumigatus, C. neoformans, M. tuberculosis and P. brasiliensis [15][16][17][18][19] as well as other fungal infections, which are typically acquired through the respiratory route. DCs have been subcategorized into 3 types; conventional myeloid, plasmacytoid, and lymphoid DCs.…”

Contribution of CD8+ T Cells to Control of Mycobacterium tuberculosis Infection

“…To offer another approach, our group previously developed mathematical models that track major elements of the cell-mediated immune response to Mtb infection (13)(14)(15). The first model accounts for the dynamics of six cell populations, including macrophages (resting, infected, and activated subpopulations) and CD4 ϩ T cells (Th0, Th1 and Th2 effector subpopulations), four cytokines (IFN-␥, IL-12, IL-10, and IL-4), and two bacterial subpopulations (intracellular and extracellular mycobacteria) (15).…”