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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 have 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 activated markedly and skewed towards a proinflammatory T helper type 1 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 CD25high hyperactivated T cells were ineffective to alleviate disease, indicating that T cell hyperactivation is not a 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 severe combined immunodeficient (SCID) mice. These data suggest that lymphocyte-independent mechanisms can underlie virus-associated secondary HLH, accentuating a clear distinction with primary HLH.<\/jats:p>","DOI":"10.1111\/cei.13084","type":"journal-article","created":{"date-parts":[[2017,11,27]],"date-time":"2017-11-27T10:59:12Z","timestamp":1511780352000},"page":"104-119","source":"Crossref","is-referenced-by-count":6,"title":["Lymphocyte-independent pathways underlie the pathogenesis of murine cytomegalovirus-associated secondary haemophagocytic lymphohistiocytosis"],"prefix":"10.1093","volume":"192","author":[{"given":"E","family":"Brisse","sequence":"first","affiliation":[{"name":"Laboratory of Immunobiology, Rega Institute, KU Leuven, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4467-9831","authenticated-orcid":false,"given":"M","family":"Imbrechts","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology, Rega Institute, KU Leuven, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T","family":"Mitera","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology, Rega Institute, KU Leuven, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J","family":"Vandenhaute","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology, Rega Institute, KU Leuven, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N","family":"Berghmans","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology, Rega Institute, KU Leuven, Leuven, Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L","family":"Boon","sequence":"additional","affiliation":[{"name":"Epirus Biopharmaceuticals Netherlands, Utrecht, the Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C","family":"Wouters","sequence":"additional","affiliation":[{"name":"Laboratory of 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