The members of tumor necrosis factor receptor (TNFR) superfamily have been designated as the "guardians of the immune system" due to their roles in immune cell proliferation, differentiation, activation, and death (apoptosis). This study reports the cloning of a new member of the TNFR superfamily, RELT (Receptor Expressed in Lymphoid Tissues). RELT is a type I transmembrane glycoprotein with a cysteine-rich extracellular domain, possessing significant homology to other members of the TNFR superfamily, especially TNFRSF19, DR3, OX40, and LTbeta receptor. The messenger RNA of RELT is especially abundant in hematologic tissues such as spleen, lymph node, and peripheral blood leukocytes as well as in leukemias and lymphomas. RELT is able to activate the NF-kappaB pathway and selectively binds tumor necrosis factor receptor-associated factor 1. Although the soluble form of RELT fusion protein does not inhibit the one-way mixed lymphocyte reaction, immobilized RELT is capable of costimulating T-cell proliferation in the presence of CD3 signaling. These results define a new member of the TNFR superfamily that may be a potential regulator of immune responses.