Selective Absence of Co‐Inhibitory Receptor‐Expressing CD4 + T Cells in Lungs of Obese House Dust Mite‐Allergic C57BL /6 Mice

ABSTRACT Background Asthma and obesity are highly prevalent chronic inflammatory diseases, the mutual pathomechanistic relationships of which have not been fully elucidated yet. We hypothesized that inflammatory mechanisms in obese adipose tissue influence the phenotype of an induced allergic airway inflammation (AAI) with altered activation processes in CD4 + T cells being involved in this interaction. Methods C57BL/6 and BALB/c mice were fed high‐fat (HFD) or normal (ND) diet for several weeks and subjected to a house dust mite (HDM)‐induced model of AAI mimicking main features of human asthma. Inflammatory and metabolic parameters were assessed and lung CD45 + cells were deep‐phenotyped using flow cytometry and targeted single cell CITE‐Seq (cellular indexing of transcriptomes and epitopes by sequencing) analysis. Results Despite comparable metabolic changes in both strains in response to HFD, only C57BL/6 mice developed excessive weight gain. In both strains, the chosen HDM exposure protocol induced a mixed AAI phenotype characterized by eosinophil and neutrophil airway infiltration in ND‐fed mice. However, only in C57BL/6 mice, concomitant HFD resulted in changed eosinophils to neutrophils ratios and a higher proportion of lung CD4 + T cells. Using single‐cell CITE‐Seq, a specific subcluster of CD4 + T cells was identified exclusively in the lungs of lean, but not in obese, HDM‐exposed C57BL/6 mice, characterized by the expression of co‐inhibitory receptors such as CTLA‐4, PD‐1, and LAG‐3. Furthermore, culturing pre‐differentiated T cells in the presence of supernatants from hypertrophic adipocytes resulted in reduced frequencies of cells expressing these receptors. Conclusion The presence of co‐inhibitory receptor‐expressing CD4 + T cells in lean mice with AAI may represent a disease‐limiting mechanism, which is abolished by a co‐existing obesity resulting in intensified inflammatory processes in the lungs. This mechanism could explain higher asthma severity observed in obese patients.