Tolerance to the neuron-specific paraneoplastic HuD antigen.
Experiments dating back to the 1940's have led to the hypothesis that the brain is an immunologically privileged site, shielding its antigens from immune recognition. The paraneoplastic Hu syndrome provides a powerful paradigm for addressing this hypothesis; it is believed to develop because small cell lung cancers (SCLC) express the neuron-specific Hu protein. This leads to an Hu-specific tumor immune response that can develop into an autoimmune attack against neurons, presumably when immune privilege in the brain is breached. Interestingly, all SCLC express the onconeural HuD antigen, and clinically useful tumor immune responses can be detected in up to 20% of patients, yet the paraneoplastic neurologic syndrome is extremely rare. We found that HuD-specific CD8+ T cells are normally present in the mouse T cell repertoire, but are not expanded upon immunization, although they can be detected after in vitro expansion. In contrast, HuD-specific T cells could be directly activated in HuD null mice, without the need for in vitro expansion. Taken together, these results demonstrate robust tolerance to the neuronal HuD antigen in vivo, and suggest a re-evaluation of the current concept of immune privilege in the brain.
DeLuca
Ilana
I
Howard Hughes Medical Institute and Laboratory of Molecular Neuro-Oncology, The Rockefeller University, New York, NY, USA.
Blachère
Nathalie E
NE
Santomasso
Bianca
B
Darnell
Robert B
RB
D019264:Adoptive Transfer; D000818:Animals; D015551:Autoimmunity; D001854:Bone Marrow Cells / Q000166:cytology; D001921:Brain / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D051959:ELAV Proteins / Q000378:metabolism*; D000939:Epitopes / Q000737:chemistry; D007668:Kidney / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D055752:Small Cell Lung Carcinoma / Q000378:metabolism*; D013154:Spleen / Q000166:cytology
D051959:ELAV Proteins; D000939:Epitopes