Instructor of Medicine

CD4 Tissue Resident Memory T Cells Promote Inflammatory Pathways Associated with Asthma
Nathan Schoettler1, Anne I Sperling1, Carole Ober2
1University of Chicago, Department of Medicine; 2University of Chicago, Department of Human Genetics

Activated CD4 T cells drive asthma pathogenesis through distinct cytokine and inflammatory pathways that have been linked to asthma phenotypes. These include Th2 and Th17 cytokines and IL-2, which drives antigen-specific T cell proliferation. However, the specific subset(s) of human lung CD4 T cells that contributes to these responses and how these T cells are activated is unknown. Features of human CD4 memory T cells differ between the lung and other sites, including higher expression of innate immune receptors, different proportion of memory subsets and distinct T cell receptor repertoires. We have characterized the responses of human lung CD4 effector memory (TEM) and tissue resident memory (TRM) T cell subsets to innate stimuli (lipopolysaccharide and poly-I:C, separately) and T cell receptor (TCR)-specific activation (anti-CD3/anti-CD28) in a total lung leukocyte cell culture model from 10 lung donors. After 20 hours of treatment, CD4 TEM and TRM T cells were sorted and RNA was extracted and sequenced for comparison of the transcriptional differences between cell types and between treatments. While there were no differences in gene expression responses between CD4 TEM and TRM cells after lipopolysaccharide or poly-I:C treatment at a false discovery rate of 5%, 424 genes were differentially expressed between CD4 TEM and TRM cells after anti-CD3/anti-CD28 treatment. Genes with higher expression in CD4 TRM cells included IL2, Th2 cytokines (IL4, IL13 and IL5) and the Th17 cytokine IL17A. Our results demonstrate that human CD4 TRM cells promote asthma-relevant responses after TCR-specific activation and that innate stimulation alone or TCR-specific activation of CD4 TEM cells does not activate these responses.