Interrogating mechanisms of CD8 T cell dysfunction in obese asthma

Abstract Pediatric obese atopic asthma (OA) is a complex and poorly understood disease at the intersection of two of the most common chronic inflammatory diseases of childhood. Pediatric OA patients often experience severe asthma exacerbations caused by respiratory viral infections. However, the immunological mechanisms by which obesity modifies immune function in asthma remain poorly understood. Using high dimensional immune profiling, we have demonstrated CD8 T cells from pediatric OA patients have an exhausted-like immunophenotype compared to non-obese asthmatics. To more deeply characterize the role of CD8 T cell dysfunction in OA, we developed a mouse model of OA using high fat diet (HFD) to induce obesity and house dust mite (HDM) to induce asthma. We found that non-naïve CD8 T cells isolated from the lungs of OA mice demonstrate increased expression of multiple activation and inhibitory receptors (e.g., PD-1, CD39 and Tim3) as well as TOX, all consistent with T cell exhaustion, compared to healthy controls. We hypothesize the exhausted-like state of CD8 T cells in OA impairs anti-viral responses, thereby increasing severity of asthma exacerbation during respiratory viral infections. Ongoing work is testing antigen specific responses to influenza infection. Overall, this reveals a previously unrecognized role for exhausted-like CD8 T cell responses in mediating the immunopathogenesis of pediatric obese asthma. This work was supported by the Translational Research Training Program in Environmental Health Sciences Pre-Doctoral Fellowship to C.A.H. and K08-AI135091 to S.E.H.