The Role of Neutrophils and T Cell Recognition of Their Conserved Arginine-Rich Protein Domains in Multiple Sclerosis
Final Report Abstract
Relapsing remitting multiple sclerosis (RRMS) develops in genetically susceptible individuals and requires environmental triggers. The nonpathogenic and ubiquitous Torque Teno virus was identified by us as a putative trigger since its poly-arginine (Arg) motif is recognized by in vivo clonally expanded cerebrospinal fluid-infiltrating T cells. These T cells can also be stimulated by Arg-rich protein domains from other viruses and autoantigens. Interestingly, very few proteins show a high content of Arg and these share specific functions such as DNA binding or killing of bacteria. Neutrophils, one of the body’s main cellular components for the destruction of microorganisms, are armed with an unusual high number of Arg-rich proteins such as bactericidal proteins and proteases with indiscriminate histotoxic potential, and to minimize tissue injury, their activation involves priming with inflammatory mediators before cells are fully activated. In this project, we demonstrate that neutrophils in MS patients are more numerous and exhibit a primed state being easily activated. The chronic inflammatory environment in RRMS probably underlies this inappropriate neutrophil priming, which may result in enhanced neutrophil activation during infection. Among their strategies to eliminate pathogens they release Neutrophil Extracellular Traps (NETs), chromatin fibers decorated with Arg-rich antimicrobial proteins that trap and kill pathogens very efficiently. Here we demonstrate that circulating NETs are elevated in RRMS male patients and, although our systematic and in depth characterization of these patients argue against a major role of circulating NETs in this disease, they suggest that NETs may underlie genderspecific differences in MS pathogenesis. Our data further show that NETs released by human neutrophils can directly prime T cells by reducing their activation threshold. NETs-mediated priming increases T cell responses to specific antigens and even to sub-optimal stimuli, which would not induce a response in resting T cells. NETs-mediated T cell activation adds to the list of neutrophil functions and demonstrates a novel link between innate and adaptive immune responses. Whether NETs prime preferentially T cells specific of Arg-rich domains and play a role in RRMS requires further investigation.
Publications
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Neutrophils in Multiple Sclerosis Are Characterized by a Primed Phenotype. Journal of Neuroimmunology 2011;242(1-2):60-71
Naegele M, Tillack K, Reinhardt S, Schippling S, Martin R, Sospedra M
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T Lymphocyte Priming by Neutrophil Extracellular Traps Links Innate and Adaptive Immune Responses. Journal of Immunology 2012;188(7):3150-9
Tillack K, Breiden P, Martin R, Sospedra M
