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Biochemical Basis for T Lymphocyte Tolerance

One of the critical barriers to effective immunization of tumor-bearing hosts to their tumors is the observation that most tumor associated antigens are self antigens that are identical in sequence to the same antigens expressed on normal tissues. Although circulating T cells recognizing such self antigens are present in virtually all individuals, they are usually anergic; that is, despite the fact that their recognition structures are intact, they fail to mount a strong immune response.

A Novel E3 Ligase: GRAIL

Understanding of the biochemical and molecular basis for anergy has been extremely limited. However, Garry Fathman's laboratory has recently discovered a gene in T cells which appears to be a key determinant of T cell anergy. Transduction of T cell hybridomas with this anergy-specific gene, a novel E3 ligase, known as GRAIL, inhibited the expression of cytokines required for T cell growth and differentiation as well as selected chemokines.

The Fathman group is currently characterizing this ubiquitin E3 ligase and its protein binding partners, at least one of which is the tumor suppressor, MCC.  At least one substrate of GRAIL is RhoGDI and its ubiquitination leads to inactivation of RHO . Interestingly, GRAIL is expressed in T cells rendered unresponsive in vivo following peptide administration in vivo.

The identification and functional characterization of GRAIL will continue during the next several years, and should provide an interesting model of cell signaling and cell biology for gene knock-out studies, gene transfer studies, and transgenic mice. The interesting relationship of cell cycle arrest driven by GRAIL opens interesting potential avenues to adaptation to analysis of immunological defects leading to cancer.

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