Pathogenic Autoreactive Th Cells Are Identified in Autoimmune Neuroinflammation by Expression of neuropilin-1 (NRP1)

Abstract Text: Many autoimmune diseases are associated with self-reactive CD4+ T helper (Th) cells generating pathogenic responses against self-tissues. Autoimmune disease treatment is restricted by a lack of ability to directly identify harmful self-reactive Th cells from beneficial Th cells that respond to foreign antigens. We have reported in several mouse models of systemic autoimmune disease that populations of self-reactive pathogenic Th cells upregulate Neuropilin-1 (NRP1), a surface receptor usually expressed only by regulatory Foxp3+ Th cells in the steady state. The NRP1+Foxp3- Th cell level correlated with disease severity and these cells were pathogenic on transfer; additionally, treatment targeting NRP1-expressing cells reduced clinical systemic autoimmune disease (Raveney et al. EMBO Mol. Med. 2022).
Immunization of mice with self-peptides, such as MOG35-55 which generates the autoimmune neuroinflammatory disease experimental autoimmune encephalomyelitis (EAE), induced novel expression of NRP1 by Foxp3- Th cells, whereas immunization with non-self-peptides did not (p < 0.0001). At peak EAE, NRP1+ Th cells formed more than 40% of CNS-infiltrating Th cells and changes in NRP1+ CNS Th cell proportion mirrored clinical disease. NRP1+ Th cells generated pathogenic responses upon restimulation with a MOG35-55 peptide, whereas NRP1- Th cells made only low responses.
Further, the presence of circulating NRP1+ Th cells was significantly associated with multiple sclerosis patient groups (p=0.004, Fishers exact test). Together these data hint a common marker for self-specific Th cells that have developed into pathogenic autoreactive Th cells. NRP1 measurement provides exciting potential for identifying and targeting harmful self-reactive Th cells even when their cognate antigen is unknown.