Regulation of Cytokine Production by Virus-Specific CD8 T Cells in the Lungs

Abstract

Inflammation and the elimination of infected host cells during an immune response often cause local tissue injury and immunopathology, which can disrupt the normal functions of tissues such as the lung. Here, we show that both virus-induced inflammation and the host tissue environment combine to influence the capacity of virus-specific CD4 and CD8 T cells to produce cytokines in various tissues. Decreased production of cytokines, such as IFN-␥ and TNF-␣, by antigen-specific T cells is more pronounced in peripheral tissues, such as the lung and kidney, than in secondary lymphoid organs, such as the spleen or lymph nodes. We also demonstrate that tissues regulate cytokine production by memory T cells independently of virus infection, as memory T cells that traffic into the lungs of naïve animals exhibit a reduced ability to produce cytokines following direct ex vivo peptide stimulation. Furthermore, we show that cytokine production by antigen-specific memory CD4 and CD8 T cells isolated from the lung parenchyma can be rescued by stimulation with exogenous peptide-pulsed antigen-presenting cells. Our results suggest that the regulation of T-cell cytokine production by peripheral tissues may serve as an important mechanism to prevent immunopathology and preserve normal tissue function.

Determining the Breadth of the Respiratory Syncytial Virus-Specific T Cell Response

“…For analysis of lung mononuclear cells, lungs were harvested from day 8 RSV-infected mice, and single-cell suspensions were generated as previously described (27). Cells (1.5 ϫ 10 6 ) were incubated with 1 M peptide (Mimotopes) identified in the initial screening experiments or synthesized peptides (Biosynthesis, Lewisville, TX) in the presence of 10 g/ml BFA for 5 h at 37°C.…”

“…Spleen cells from day 8 RSV-infected mice were harvested and single-cell suspensions were generated as previously described (27). Splenocytes (1.5 ϫ 10 6 ) were incubated with 1 M peptide from an overlapping peptide library (15-mers overlapping every 10 amino acids), spanning the entirety of the RSV-A2-proteome (Mimotopes Pty.…”

Differentiation-Dependent Differences in Murine T Cell Susceptibility to Negative Regulation by the Lung

“…Thus, the lung exerts potent immunoregulatory effects on effector T cells. The observed nonresponsiveness encompasses all effector functions assessed (i.e., IFN-g and TNF-a production, as well as secretion of lytic granules [1][2][3][4][5]). Upon further observation, we discovered that the CD8 1 T cell inactivation is unique to the parenchymal compartment of the lung, as CD8 1 effector cells from the airway compartment maintain their functional capabilities (6).…”

“…This phenomenon has since been observed in other studies (5). This nonresponsiveness encompasses all effector functions assessed (i.e., IFN-g and TNF-a production), as well as secretion of lytic granules (1).…”

“…These cells, upon reaching the lung, exert potent effector functions, including the release of IFNg and TNF-a, as well as the ability to lyse infected cells. Past studies, including those with respiratory syncytial virus, mouse pneumovirus, and simian virus (SV) 5, have reported that virusspecific CD8 1 effector T cells entering the lung as a result of respiratory infection undergo significant loss of function (1)(2)(3)(4)(5). These cells have not altered their cytokine profile from typical Tc1 cells, as they produce neither IL-4 nor IL-10 (Refs.…”