Elastin receptor (S-gal) occupancy by elastin peptides modulates T cell response during murine emphysema

Chronic obstructive pulmonary disease and emphysema are associated with increased elastin peptides (EP) production due to excessive breakdown of lung connective tissue. We recently reported that exposure of mice to EP elicited hallmark features of emphysema. EP effects are largely mediated through a receptor complex which includes the elastin-binding protein S-gal. In previous studies, we established a correlation between cytokine production and S-gal protein expression in EP treated immune cells. In this study, we investigated the S-gal-dependent EP effects on T helper (Th) and T cytotoxic (Tc) responses during murine EP-triggered pulmonary inflammation. C57BL/6J mice were endotracheally instilled with the VGVAPG elastin peptide and 21 days after treatment, local and systemic T lymphocyte phenotypes were analyzed at cytokine and transcription factor expression levels by multicolor flow cytometry. Exposure of mice to the VGVAPG peptide resulted in a significant increase in the proportion of the CD4+ and CD8+ T cells expressing the cytokines IFN- or IL-17a and the transcription factors Tbet or RORt without effects on IL-4 and Gata3 expression. These effects were maximized when each T cell sub-population was challenged ex vivo with EP and they were inhibited in vivo when an analogous peptide antagonizing the EP/S-gal interactions was instilled together with the VGVAPG peptide. This study demonstrates that during murine emphysema, EP/S-gal interactions contribute to a Th-1 and Th-17 pro-inflammatory T cell response combined with a Tc-1 response. Our study also highlights the S-gal receptor as a putative pharmacological target to modulate such an immune response.

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