{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T16:08:59Z","timestamp":1787069339244,"version":"build-2736575974"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Visceral leishmaniasis (VL), caused by Leishmania donovani, is characterized by progressive immune dysregulation that supports parasite persistence. The CD40\u2013CD40L axis is essential for antigen-presenting cell (APC) licensing and Th1-mediated nitric oxide-dependent parasite control; however, how its function evolves during infection remains incompletely understood. Here, we define the temporal regulation and functional polarity of CD40 signalling during experimental VL. Using BALB\/c mice and primary macrophage assays, we investigated the temporal regulation of CD40 signalling during experimental VL. CD40 expression, cytokine production, nitric oxide levels, antibody responses, T-cell phenotypes, immune checkpoint expression, and macrophage activation were evaluated during progressive infection. Functional studies included CD40 agonism, CD40 knockdown, and TRAF-selective CD40 reconstitution to assess stage-specific effects on parasite control and immune regulation. Increasing parasite burden drove a gradual shift in CD40 signalling from protective to suppressive outcomes. In vitro infection reduced CD40 expression and IL-12 production while increasing IL-10, indicating early impairment of APC licensing. In vivo, progressive splenic infection was associated with diminished nitric oxide production, a declining IgG2a\/IgG1 ratio, expansion of GATA3+ Th2 and FOXP3+ regulatory T-cell populations, and increased PD-L1 and TIM-3 expression, consistent with a regulatory and exhausted immune environment. Despite partial recovery of CD40 expression on myeloid APCs at later stages, declining CD40L+ T-cell availability and sustained IL-10\/Arg1 signalling limited functional responsiveness. Early CD40 agonism failed to restore parasite control, whereas late activation exacerbated disease. CD40 knockdown increased parasite burden and reduced iNOS+ macrophages, confirming the requirement for CD40-dependent licensing. Finally, TRAF2-biased CD40 signalling promoted macrophage activation and parasite restriction, whereas TRAF6-biased signalling reinforced immunosuppression. These findings identify a stage-dependent functional threshold beyond which CD40 signalling no longer sustains protective immunity during VL, highlighting the importance of restoring APC competence and selectively directing CD40 signalling through TRAF2-linked pathways.<\/jats:p>","DOI":"10.1093\/cei\/uxag045","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T11:38:19Z","timestamp":1785843499000},"source":"Crossref","is-referenced-by-count":0,"title":["Stage-dependent CD40 signalling defines a shift between protective and suppressive immunity in visceral leishmaniasis"],"prefix":"10.1093","volume":"220","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0181-2102","authenticated-orcid":false,"given":"Hima","family":"Mahor","sequence":"first","affiliation":[{"name":"National Centre for Cell Science , Savitribai Phule Pune University, Ganeshkhind, Pune, Maharashtra 411007 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bhaskar","family":"Saha","sequence":"additional","affiliation":[{"name":"National Centre for Cell Science , Savitribai Phule Pune University, Ganeshkhind, Pune, Maharashtra 411007 ,","place":["India"]},{"name":"JSPS-GHMC , Hyderabad 500 013, Telangana ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"2026081810520136600_uxag045-B1","doi-asserted-by":"crossref","first-page":"e35671","DOI":"10.1371\/journal.pone.0035671","article-title":"Leishmaniasis worldwide and global estimates of its incidence","volume":"7","author":"Alvar","year":"2012","journal-title":"PLoS One"},{"key":"2026081810520136600_uxag045-B2"},{"key":"2026081810520136600_uxag045-B3","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1016\/j.chom.2011.03.011","article-title":"Imaging host cell-Leishmania interaction dynamics implicates parasite motility, lysosome recruitment, and host cell wounding in the infection process","volume":"9","author":"Forestier","year":"2011","journal-title":"Cell Host Microbe"},{"key":"2026081810520136600_uxag045-B4","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1084\/jem.20022033","article-title":"CD40 signaling is impaired in Leishmania major-infected macrophages and is rescued by p38 MAPK activator, establishing a host-protective memory T-cell response","volume":"197","author":"Awasthi","year":"2003","journal-title":"J Exp Med"},{"key":"2026081810520136600_uxag045-B5","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/ni.1705","article-title":"Cholesterol depletion associated with Leishmania major infection alters macrophage CD40 signalosome composition and effector function","volume":"10","author":"Rub","year":"2009","journal-title":"Nat 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