While investigating immune responses to the autoantigen cerebellar degeneration-related protein 2 (CDR2), Blachère et al. discovered that tolerance to this predominantly cerebellum-expressed protein was enhanced by expression and presentation by T cells, resulting in anergy of interacting CD8+ cytotoxic T cells. This observation was extended to viral antigens presented by T cells, and the researchers speculate it is a homeostatic mechanism to prevent T cell fratricide targeted to rearranged, novel TCR CDR3 regions.
In the course of modeling the naturally occurring tumor immunity seen in patients with paraneoplastic cerebellar degeneration (PCD), we discovered an unexpectedly high threshold for breaking CD8+ cytotoxic T cell (CTL) tolerance to the PCD autoantigen, CDR2. While CDR2 expression was previously found to be strictly restricted to immune-privileged cells (cerebellum, testes, and tumors), unexpectedly we have found that T cells also express CDR2. This expression underlies inhibition of CTL activation; CTLs that respond to epithelial cells expressing CDR2 fail to respond to T cells expressing CDR2. This was a general phenomenon, as T cells presenting influenza (flu) antigen also fail to activate otherwise potent flu-specific CTLs either in vitro or in vivo. Moreover, transfer of flu peptide-pulsed T cells into flu-infected mice inhibits endogenous flu-specific CTLs. Our finding that T cells serve as a site of immune privilege, inhibiting effector CTL function, uncovers an autorepressive loop with general biologic and clinical relevance.
Author Info: (1) Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York, USA. Howard Hughes Medical Institute, New York, New York, USA. (2) Laboratory of Molecul
Author Info: (1) Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York, USA. Howard Hughes Medical Institute, New York, New York, USA. (2) Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York, USA. Division of Rheumatology, Hospital for Special Surgery, New York, New York, USA. New York Genome Center, New York, New York, USA. (3) Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York, USA. CHDI Management/CHDI Foundation, New York, New York, USA. (4) Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York, USA. Memorial Sloan-Kettering Cancer Center, New York, New York, USA. (5) Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York, USA. (6) Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York, USA. Genentech, Inc., South San Francisco, California, USA. (7) Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York, USA. (8) Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York, USA. Department of Chemistry and Life Sciences, United States Military Academy, West Point, New York, USA. (9) Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York, USA. (10) Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York, USA. (11) Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York, USA. New York Genome Center, New York, New York, USA. (12) Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York, USA. Regeneron Pharmaceuticals, Tarrytown, New York, USA. (13) Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, New York, USA. Howard Hughes Medical Institute, New York, New York, USA. New York Genome Center, New York, New York, USA.
