{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T06:05:23Z","timestamp":1784786723298,"version":"3.55.0"},"reference-count":66,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>The tumor necrosis factor (TNF) and TNF receptor (TNFR) superfamilies comprise 47 proteins that regulate immune signaling and T cell costimulation. While TNF inhibitors are established therapies for immune-mediated inflammatory diseases (IMIDs), their efficacy is limited by primary non-response and secondary loss of efficacy. Preclinical data suggest that the TNF\/TNFR members exhibit redundant and synergistic signaling, motivating combination targeting strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We have systematically evaluated TNF\/TNFR combinations as potential immunotolerance targets using integrated computational and experimental approaches. We applied a gene prioritization framework incorporating transcriptomics, genetics, druggability, and pathway regulation data to derive disease association scores for the TNF\/TNFR genes in rheumatoid arthritis and inflammatory bowel disease. Based on these scores and T cell expression profiling, ten targets were prioritized for a combinatorial screen using clinical-stage and preclinical pharmacological inhibitors in a mixed lymphocyte reaction (MLR) assay. The effects of the most promising combinations were further characterized by RNA sequencing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The combinatorial screen identified four drug combinations that significantly suppressed T cell production of IL-2 and IFN-\u03b3: TNF+CD40L, TNF+OX40L, CD40L+OX40L, and CD40L+LT\u03b2\/LIGHT. Transcriptional profiling revealed that these combinations broadly downregulated genes associated with T cell activation, proliferation, differentiation, and cytokine production that were induced during the allogeneic response. Notably, the co-inhibition of TNF and CD40L (Adalimumab+Dapirolizumab) produced the most robust suppression, uniquely downregulating 337 genes enriched for key T cell activation pathways, including NF-\u03baB and ERK1\/2.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings demonstrate that the combinatorial antagonism of TNF\/TNFR superfamily members can potently suppress allogeneic T cell responses, with the TNF+CD40L combination showing particularly strong and broad effects. The results support the continued preclinical evaluation of combinatorial TNF\/TNFR inhibition as a potential tolerance-inducing therapeutic strategy for patients with refractory IMIDs.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1867995","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T05:37:23Z","timestamp":1784785043000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Combination antagonism of TNF superfamily signaling for T cell immunosuppression"],"prefix":"10.3389","volume":"17","author":[{"given":"Praveen Krishna","family":"Veerasubramanian","sequence":"first","affiliation":[{"name":"Inflammation and Immunology Research Unit, Pfizer Research and Development","place":["Cambridge, MA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenlan","family":"Zang","sequence":"additional","affiliation":[{"name":"Inflammation 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