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In this work we expanded upon a study from our group where a ligand-based TNF-α mutein was developed to engage specifically TNFR2 and not TNFR1 activating Tregs and expanding them, which in an allo-HCT context conferred protection from GvHD. Fusing TNF trimers to the heavy chain of an Fc-dead and mouse irrelevant antibody, a new generation of this agonist was developed called NewSTAR2. It is believed that other members of the TNFSF can also target Tregs, therefore additional agonists against DR3 and GITR were developed under the same principles as for NewSTAR2. Phenotyping analysis of the expression of these three receptors were done to confirm their specificity for Tregs before in vitro and in vivo testings with mice or murine splenic cells. A potent expansion of Tregs was seen with NewSTAR2 and the other agonists as well as upregulation of activation markers on Tregs. Thorough analyses with NewSTAR2-treated mice showed how Tregs in several immune and non-immune organs were expanded and upregulated immunomodulatory receptors. A miniature suppressive assay and other cocultures with responder cells confirmed their enhanced suppression over unstimulated Tregs through contact dependent and independent mechanisms. Despite other myeloid cells also being increased after treatment, no undesired effects were observed under steady-state and prophylactic administration of a single dose of NewSTAR2 improved survival frequencies and lessened development of clinical symptoms. Prophylactic treatment with the other TNFRSF agonists showed similar protection yet Fc(DANA)-muTL1A was superior in in terms of less death events and lower clinical score. It was found that not all the three TNFSF members have redundant functions as development of skin lesions was observed with GITRL-based agonist Fc(DANA)-muGITRL, although its expansion of Tregs in steady-state was remarkable with no apparent adverse effects. Neither agonist had an impact on donor cell engraftment or allorective T cell response, however NewSTAR2-treatmend proved to reduce inflammation in small intestine and liver. This work is proof of concept of the effectivity of selectively engaging TNFSF to activate Tregs and expand them systemically allowing them to control strong and complex immune interactions like those governing GvHD.