Characterisation of the human lung fibroblasts ability to act as an antigen presenting cell for T helper cells of the immune system

Abstract

T helper cells of the immune system are critical in mediating immune responses in the lung. Through the release of cytokines, T helper cells direct the wider immune response against a range of pathogens and are considered indispensible for effective immunity. T cell activation is governed by the interaction with antigen-presenting cells (APCs), which mediate antigen-specific T cell activation and thus control immune responses in areas such as the lung. While T helper cell activation by APCs such as dendritic cells is well established, the role of fibroblasts in T helper cell activation in the lung is poorly understood. Fibroblast antigen presentation was hypothesised to be a mechanism leading to activation of bacterial-specific lung T helper cells.

Characterisation of T cell populations within the human distal lung was carried out. focusing upon examining the memory T cell populations. In addition, the cytokine production profile of T cells as a whole population and in response to specific lung bacterial antigen was examined.

Distal lung T cells were primarily CD4 T helper cells of an effector memory phenotype. IFNγ producing, Th1-type cells were the most abundant effector subset present in all T cell populations examined, while initial responses to the common lung bacteria nontypeable haemophilus influenza were more heterogeneous.

Human lung fibroblasts obtained from the distal lung were examined for expression of immune synapse molecules both ex vivo and in vitro using flow cytometry. The ability of lung fibroblasts to internalize environmental antigen was also investigated via flow cytometry and confocal microscopy. Using autologous lung fibroblasts and T helper cells, the ability of fibroblasts to present bacterial antigens non-typeable haemophilus influenza was examined. T helper activation was measured via the production of cytokines associated with the major T helper effector subsets.

Lung fibroblasts expressed HLA-DR ex vivo, and were shown to upregulate HLA-DR and ICAM-1 by IFNγ treatment in vitro, but did not express CD80 or CD86. Fibroblasts were also able to internalize environmental antigen. Fibroblasts exposed to both IFNγ and a heat-killed form of non-typeable haemophilus influenza are shown to activate IFNγ and IL-17A producing T helper cells in an antigen dependent manner.

This study demonstrates that lung fibroblasts are able to function as an inducible APC and activate proinflammatory T helper cells. This previously unknown relationship between fibroblast and T cell may represent a key mechanism in lung immune responses to bacterial populations.

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