Clonal deletion of major histocompatibility complex class I‐restricted CD4⁺CD8⁺ thymocytes in vitro is independent of the CD95 (APO‐1/Fas) ligand

Abstract

The CD95 (APO-1/Fas) ligand (CD95L) mediates apoptosis in sensitive target cells, Ca(2+)-independent cytotoxicity of cells from perforin knock-out mice, and peripheral deletion of activated T cells through engagement of its cognate receptor CD95. Double-positive thymocytes show a high constitutive expression of CD95. Therefore, we used a model system and investigated whether negative selection through apoptosis might involve CD95/CD95L. We analyzed whether CD95L may induce antigen-specific deletion of double-positive thymocytes from mice transgenic for a lymphocytic choriomeningitis virus (LCMV)/H2b-specific T cell receptor (TCR). These cells are deleted in vitro upon addition of the LCMV-peptide 33-41 in a major histocompatibility complex-class I-restricted fashion. Deletion was not blocked by soluble mouse and human CD95-Fc receptor decoys. CD95-Fc receptor decoys, however, were effective in blocking apoptosis induced by mouse CD95L-transfected L929 cells in sensitive CD95+ target cells and in thymocytes. These results suggest that TCR-induced deletion of immature thymocytes in vitro is independent of CD95L. Thus, our data argue against a role of CD95L in negative selection of MHC-class I-restricted autoreactive thymocytes.

Regulation of T cell Apoptosis during the Immune Response

“…A number of receptors of the tumor necrosis factor receptor (TNF-R) superfamily have been implicated to be involved in negative selection of thymocytes [76]. Although immature CD4 + 8 + thymocytes express CD95 (APO-1/Fas) and are susceptible to apoptosis induced by agonistic anti-CD95 antibodies [77], recombinant soluble CD95 ligand (CD95L) [13] and cell surface-bound CD95L [78], their involvement in negative selection is controversial discussed. TCRmediated thymocyte deletion of CD95-deficient (lpr) or CD95 ligand-deficient (gld) mice in response to specific antigen or superantigen is normal, suggesting that the CD95-system is not required for negative selection [79][80][81][82][83][84].…”

Studies of the mechanism of cytolysis by tumour-infiltrating lymphocytes

“…Although the literature is replete with articles using murine models, including knock-out and transgenic animals, which describe the contributions of perforin and Fas-mediated lysis in the rejection of allografts [2], in the pathogenesis of viral [3,4] and autoimmune diseases [5], and in a few instances against leukaemic malignant cells [6,7], the question of which lytic pathways are taken by TIL in the destruction of solid tumours has rarely been addressed [8]. Thus, although there is much data to suggest that tumours may escape from immune recognition by a variety of pathways, there is no evaluation of the contribution of the Fas versus the perforin and granzyme pathways in the lysis of solid tumours by human TIL.…”

Specific Cleavage of Mcl-1 by Caspase-3 in Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL)-induced Apoptosis in Jurkat Leukemia T Cells

“…However, negative selection at least of early thymocytes is normal in mice deficient for other TNF superfamily members, such as TNF or TNF receptor (31,32), Fas or Fas ligand (33,34), and more importantly components of deathinducing signaling complex, Fas-associated death domain protein (35,36), or caspase-8 (37). Given the more important role of Mcl-1 than that of Bcl-2 and Bcl-X L in lymphocyte development (38), there might exist a functional link between TRAIL and the antiapoptotic function of Mcl-1.…”