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

Abstract

Tuberculosis is the number one cause of death due to infectious disease in the world today. Understanding the dynamics of the immune response is crucial to elaborating differences between individuals who contain infection vs those who suffer active disease. Key cells in an adaptive immune response to intracellular pathogens include CD8+ T cells. Once stimulated, these cells provide a number of different effector functions, each aimed at clearing or containing the pathogen. To explore the role of CD8+ T cells in an integrative way, we synthesize both published and unpublished data to build and test a mathematical model of the immune response to Mycobacterium tuberculosis in the lung. The model is then used to perform a series of simulations mimicking experimental situations. Selective deletion of CD8+ T cell subsets suggests a differential contribution for CD8+ T cell effectors that are cytotoxic as compared with those that produce IFN-γ. We also determined the minimum levels of effector memory cells of each T cell subset (CD4+ and CD8+) in providing effective protection following vaccination.

The Effects of HIV-1 Infection on Latent Tuberculosis

“…Host shows containment of infection and enters latency after approximately 120 days (4 months). These simulations agree with those published in [55]. Parameter set shown in Tables 2-4.…”

“…During active TB, we observe growing intracellular and extracellular bacterial levels, and, compared to latent infection, a heightened immune response evidenced by significantly greater activated and infected macrophage and T-cell numbers and cytokine levels. These two results compare qualitatively and quantitatively well with the latent and active TB results published previously [55]. As seen in Figure 3, after 200 days the extracellular bacteria burden increases to levels that are no longer biologically relevant as the host would die of bacterial sepsis given bacterial loads this high.…”

“…We estimate these parameters based on corresponding parameters available for Mtb infection alone, c 52 M and k 52 M respectively. The half-saturation constant related to the effect of IL-γ on macrophage activation, s 1 , is chosen to calibrate activated macrophage dynamics with those previously published [55]. We realize that these parameter estimates may or may not be accurate and that experimental verification is still needed.…”

“…Our model could be used to investigate under what conditions viremia in the lung persists, for example by including an intrinsic antiviral activity in the lung such as defensins or surfactants, or by more closely examining the role of infected macrophages in viral replication to see if macrophage infection controls the switch in the virus tropism (i.e., its choice of macrophages versus T-cells as the preferred host cell) during infection. Including additional physiological compartments, for example blood and lymph node, can assist in refining this model as we have done previously [48] [55], [8], and [27]. The following parameters were estimated specifically for this study.…”

Human CD8+ T cells drive Th1 responses through the differentiation of TNF/iNOS‐producing dendritic cells

“…This highlights a novel role that allows the transmission of CD8 1 T-cell-mediated Th1-inducing signals without the need for physical interaction with infiltrating monocytes, similar to other bystander-mediated crosstalk seen in infectious models [23,24]. This may also explain the importance of CD8 1 T cells in microbial infections [10][11][12]25], since TNF-a and NO production by Tip-DCs are key effectors in pathogen clearance [3].…”