Manning the Barricades: Lung Fibroblasts and CD4+ T Cells as the Last Line of Defense against Bacterial Invasion?

Fibroblasts are a major structural cell in the human lung, being responsible for the production of extracellular matrix components that provide the intricate structure necessary for correct lung function. Generally located in the submucosa, fibroblasts do not usually directly interact with the commensal microbes that we now know are resident in the airways. However, during situations in which alveolar macrophages and epithelial cells are impaired, for example, during severe viral infections leading to pneumonia, bacteria can invade the lung mesenchyme. In these circumstances, fibroblasts may represent another immunological barrier to bacterial invasion, not just as innate immune effectors, but also by interacting with migrating and tissue-resident adaptive immune cell populations, such as CD4+ T cells. The cytokines produced by CD4+ T helper cells are integral in directing appropriate innate and adaptive immune responses against bacteria, but the nature of fibroblast-CD4+ cell interaction, unlike the CD8+ T-cell interaction, is not clearly established. Here, we review the responses of lung fibroblasts to bacteria and discuss emerging data indicating a key role for these cells in directly presenting bacterial antigens to CD4+ T cells.

Human Lung Fibroblasts Present Bacterial Antigens to Autologous Lung Th Cells.

Lung fibroblasts are key structural cells that reside in the submucosa where they are in contact with large numbers of CD4+ Th cells. During severe viral infection and chronic inflammation, the submucosa is susceptible to bacterial invasion by lung microbiota such as nontypeable Haemophilus influenzae (NTHi). Given their proximity in tissue, we hypothesized that human lung fibroblasts play an important role in modulating Th cell responses to NTHi. We demonstrate that fibroblasts express the critical CD4+ T cell Ag-presentation molecule HLA-DR within the human lung, and that this expression can be recapitulated in vitro in response to IFN-γ. Furthermore, we observed that cultured lung fibroblasts could internalize live NTHi. Although unable to express CD80 and CD86 in response to stimulation, fibroblasts expressed the costimulatory molecules 4-1BBL, OX-40L, and CD70, all of which are related to memory T cell activation and maintenance. CD4+ T cells isolated from the lung were predominantly (mean 97.5%) CD45RO+ memory cells. Finally, cultured fibroblasts activated IFN-γ and IL-17A cytokine production by autologous, NTHi-specific lung CD4+ T cells, and cytokine production was inhibited by a HLA-DR blocking Ab. These results indicate a novel role for human lung fibroblasts in contributing to responses against bacterial infection through activation of bacteria-specific CD4+ T cells.

Analysis of the skin of mice humanized for the immune system.

Development of new immunotherapeutic strategies relies on the ability to activate the right cells at the right place and at the right moment and on the capacity of these cells to home to the right organ(s). Skin delivery has shown high potency for immunotherapeutic administration. However, an adequate in vivo model of human skin immunity is still a critical bottleneck. We demonstrated here that the skin of human immune system mice is colonized by human hematopoietic cells, mainly human T cells and that complementation with human antigen-presenting cells at the vaccination site allowed the induction of an immune response.

The prescribed duration algorithm: utilising 'free text' from multiple primary care electronic systems.

PURPOSE: To develop and test an algorithm that translates total dose and daily regimen, inputted as 'free text' on a prescription, into numerical values to calculate the prescribed treatment duration. METHOD: The algorithm was developed using antibiotic prescriptions (n = 711,714) from multiple primary care computer systems. For validation, the prescribed treatment duration of an independent sample of antibiotic scripts was calculated in two ways: (a) computer algorithm, (b) manually reviewed by a researcher blinded to the results of (a). The outputs of the two methods were compared and the level of agreement assessed, using confidence intervals for differences in proportions. This was repeated on sample of antidepressant scripts to test generalisability of the algorithm. RESULTS: For the antibiotic prescriptions, the algorithm processed 98.5% with an accuracy of 99.8% and the manual review processed 98.5% with 98.9% accuracy. The differences between these proportions are 0.0% (95%CI of -0.9, 0.9%) and 1.0% (95%CI of -0.1, 2.3%), respectively. For the antidepressant prescriptions, the algorithm processed 91.5% with an accuracy of 96.6% compared to the manual review with 96.4% processed and 99.8% accuracy; difference between these proportions is 4.9% (95%CI of 2.0, 8.0%) and 3.2% (95%CI of 1.6, 5.3%), respectively. CONCLUSION: The algorithm proved to be applicable and efficient for assessing prescribed duration, with sensitivity and specificity values close to the manual review, but with the added advantage that the computer can process large volume of scripts rapidly and automatically.