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4-1BB, a member of the tumor necrosis factor receptor(TNFR) superfamily, is a major costimulatory receptorthat is rapidly expressed on the surface of CD4+ andCD8+ T cells after antigen- or mitogen-induced activation. The interaction of 4-1BB with 4-1BBL regulatesimmunity and promotes the survival and expansion ofactivated T cells. In this study, the expression of 4-1BBand 4-1BBL was examined during regeneration of themurine thymus following acute cyclophosphamideinducedinvolution. Four-color flow cytometry showedthat 4-1BB and 4-1BBL were present in the normal thymusand were preferentially expressed in the regeneratingthymus, mainly in CD4+CD8+ double-positive(DP) thymocytes. Furthermore, the CD4loCD8lo,CD4+CD8lo and CD4loCD8+ thymocyte subsets, representingstages of thymocyte differentiation intermediatebetween DP and single-positive (SP) thymocytes,also expressed 4-1BB and 4-1BBL during thymusregeneration but to a lesser degree. Interestingly,the 4-1BB and 4-1BBL positive cells among theCD4+CD8+ DP thymocytes present during thymus regenerationwere TCRhi and CD69+ unlike the correspondingcontrols. Moreover, the 4-1BB and 4-1BBLpositive cells among the intermediate subsets presentduring thymus regeneration also exhibited TCRhi/intand CD69+/int phenotypes, indicating that 4-1BB and4-1BBL are predominantly expressed by the positivelyselected population of the CD4+CD8+ DP and the intermediatethymocytes during thymus regeneration. RT-PCR and Western blot analyses confirmed the presenceand elevated levels of 4-1BB and 4-1BBL mRNAand protein in thymocytes during thymus regeneration. We also found that the interaction of 4-1BB with4-1BBL promoted thymocyte adhesion to thymic epithelialcells. Our results suggest that 4-1BB and4-1BBL participate in T lymphopoiesis associated withpositive selection during recovery from acute thymicinvolution.
