Neutrophils direct T cell function during inflammation
Event details
As adaptive immune responses develop, T cells proliferate in the lymph nodes then migrate into tissue sites of inflammation where they receive further signals from resident cells. At all of these sites - lymph nodes, lymphatics, blood, and tissues - neutrophils are present. Neutrophils are the most abundant leukocyte in human blood, patrol lymph nodes, and flood into tissues rapidly following infectious or sterile inflammation. This means that T cells encounter large numbers of neutrophils throughout their differentiation and effector function. In addition, neutrophils NETose, de-granulate, and die, meaning their intracellular contents are released in high local concentration. As a result, T cells moving into inflamed tissues are swimming through a sea of neutrophil mediators - and yet we have almost no idea what this does to the T cell phenotype or function.
In my lab, we examine how neutrophilia alters T cell differentiation in a number of models of inflammatory disease. In particular, we study one peptide, cathelicidin, which is released from neutrophil secondary granules at high concentration and is present on NETs. We have found that cathelicidin release by neutrophils drives Th17 differentiation through potentiation of TGF-β signalling, in an aryl hydrocarbon receptor-dependent fashion. In CD8+ T cells, it specifically suppresses blimp1 and eomesodermin, leading to down-regulation of granzymes and IFN-γ.
Now, our new data shows that this does not only occur during acute models - but that long-term inflammatory disease is also characterised by cathelicidin expression and Th17 promotion. We demonstrate that cathelicidin is released in the central nervous system during EAE and in patients with Multiple Sclerosis, and that this drives pathogenic T cell development. We propose that neutrophil-T cell interactions are frequent and important for driving T cell phenotype. Developing better models to understand and study these interactions is necessary as we understand their impact on human inflammatory disease.