Lymphocyte-independent pathways underlie the pathogenesis of murine cytomegalovirus-associated secondary hemophagocytic lymphohistiocytosis

Summary

Hemophagocytic lymphohistiocytosis (HLH) constitutes a spectrum of immunological disorders characterized by uncontrolled immune activation and key symptoms such as fever, splenomegaly, pancytopenia, hemophagocytosis, hyperferritinemia and hepatitis. In genetic or primary HLH, hyperactivated CD8⁺ T cells are the main drivers of pathology. However, in acquired, secondary HLH, the role of lymphocytes remains vague. In the present study the involvement of lymphocytes in the pathogenesis of a cytomegalovirus-induced model of secondary HLH was explored. We previously reported CD8⁺ T cells to be redundant in this model and therefore focused on CD4⁺ helper and regulatory T cells. CD4⁺ T cells were markedly activated and skewed towards a pro-inflammatory T_helper1 transcription profile in mice displaying a severe and complete HLH phenotype. Counter to expectations, regulatory T cells were not reduced in numbers and were in fact more activated. Therapeutic strategies targeting CD25^high hyperactivated T cells were ineffective to alleviate disease, indicating that T cell hyperactivation is no pathogenic factor in cytomegalovirus-induced murine HLH. Moreover, even though T cells were essential in controlling viral proliferation, CD4⁺ T cells, in addition to CD8⁺ T cells, were dispensable in the development of the HLH-like syndrome. In fact, no T or B cells were required for induction and propagation of HLH disease, as evidenced by the occurrence of cytomegalovirus-associated HLH in SCID mice. These data suggest that lymphocyte-independent mechanisms can underlie virus-associated secondary HLH, accentuating a clear distinction with primary HLH. This article is protected by copyright. All rights reserved.