Alexander Muselman

All Publications

• Erythropoietin receptor on cDC1s dictates immune tolerance. Nature Zhang, X., McGinnis, C. S., Yu, G., Chen, S., Zheng, P., Schürch, C. M., Hiam-Galvez, K. J., Reticker-Flynn, N. E., Guo, W., Yao, W., Qiu, J., Muselman, A., Linde, I. L., Hickey, J. W., Yan, H., Tran, V. M., Qiu, W., Brichart-Vernos, D., Hirai, T., Yu, B., An, X., Xiao, Y., Paidassi, H., Scharschmidt, T. C., Angelo, M., Sheppard, D., Chi, H., Satpathy, A. T., Way, S. S., Malissen, B., Strober, S., Engleman, E. G. 2025

  Abstract

  Type 1 conventional dendritic cells (cDC1s) are unique in their efferocytosis1 and cross-presenting abilities2, resulting in antigen-specific T cell immunity3 or tolerance4-8. However, the mechanisms that underlie cDC1 tolerogenic function remain largely unknown. Here we show that the erythropoietin receptor (EPOR) acts as a critical switch that determines the tolerogenic function of cDC1s and the threshold of antigen-specific T cell responses. In total lymphoid irradiation-induced allograft tolerance9,10, cDC1s upregulate EPOR expression, and conditional knockout of EPOR in cDC1s diminishes antigen-specific induction and expansion of FOXP3+ regulatory T (Treg) cells, resulting in allograft rejection. Mechanistically, EPOR promotes efferocytosis-induced tolerogenic maturation7,11 of splenic cDC1s towards late-stage CCR7+ cDC1s characterized by increased expression of the integrin β8 gene12 (Itgb8), and conditional knockout of Itgb8 in cDC1s impairs tolerance induced by total lymphoid irradiation plus anti-thymocyte serum. Migratory cDC1s in peripheral lymph nodes preferentially express EPOR, and their FOXP3+ Treg cell-inducing capacity is enhanced by erythropoietin. Reciprocally, loss of EPOR enables immunogenic maturation of peripheral lymph node migratory and splenic CCR7+ cDC1s by upregulating genes involved in MHC class II- and class I-mediated antigen presentation, cross-presentation and costimulation. EPOR deficiency in cDC1s reduces tumour growth by enhancing anti-tumour T cell immunity, particularly increasing the generation of precursor exhausted tumour antigen-specific CD8+ T cells13 in tumour-draining lymph nodes and supporting their maintenance within tumours, while concurrently reducing intratumoural Treg cells. Targeting EPOR on cDC1s to induce or inhibit T cell immune tolerance could have potential for treating a variety of diseases.

  View details for DOI 10.1038/s41586-025-09824-z

  View details for PubMedID 41372415

  View details for PubMedCentralID 10931539

• Early antiviral treatment following gammaherpesvirus-68 infection of the central nervous system prevents subsequent multiple sclerosis-like disease. Journal of neuroinflammation Muselman, A., Kongara, S., Hsu, N., Aggarwal, A., Yu, J., Rajadas, J., Engleman, E. G. 2025; 22 (1): 228

  Abstract

  Growing evidence indicates that Epstein-Barr virus (EBV), a gammaherpesvirus, plays a central role in the pathogenesis of multiple sclerosis (MS). The presence of EBV-infected cells in the central nervous system (CNS) of MS patients, but not in neurologically healthy individuals, suggests that viral persistence in the CNS may drive MS. However, why there is such a long interval between initial infection and the development of disease is unknown.To model the effects of EBV infection on the brain, we intracerebrally infected mice with murine gammaherpesvirus-68 (MHV68), a virus genetically related to EBV that causes transient pathology strikingly similar to that seen in humans after acute EBV infection. One month following MHV68 infection, we administered myelin oligodendrocyte glycoprotein (MOG) peptide to evaluate the effects of prior MHV68 infection on the response to an additional inflammatory stimulus of the CNS. Virus persistence, microglial activation and immune cell infiltration were evaluated over time using flow cytometry.Intracerebral MHV68 infection induced mild brain demyelination and ataxia, a common symptom of MS, that both quickly resolved. However, administration of MOG peptide one month later led to more severe brain demyelination and more sustained ataxia, suggesting that prior MHV68 infection sensitized the mice to a newly introduced immune stimulus. Further investigation revealed that following CNS infection, MHV68 persisted in microglia, where it induced a primed phenotype marked by elevated MHC-II expression and heightened immune reactivity for at least six months. Primed microglia displayed increases in the labile iron pool, and iron chelation reduced microglial priming. Early antiviral treatment during MHV68 infection completely prevented subsequent MOG-induced demyelinating disease.These findings support a two-step mechanism by which CNS infection with a gammaherpesvirus closely related to EBV sensitizes the host to a second unrelated immune stimulus that triggers MS-like disease manifestations. Chronic priming of microglia resulting from the initial infection contributes to this process, and prevention of such priming with early antiviral treatment also prevents neuropathology following the second stimulus. EBV infection may similarly sensitize humans to a second stimulus and, if so, treatment of acute EBV infection may avert subsequent MS development.

  View details for DOI 10.1186/s12974-025-03547-8

  View details for PubMedID 41063265

  View details for PubMedCentralID 5830904