T cells presenting viral antigens or autoantigens induce cytotoxic T cell anergy
Nathalie E. Blachère, Dana E. Orange, Emily C. Gantman, Bianca D. Santomasso, Graeme C. Couture, Teresa Ramirez-Montagut, John Fak, Kevin J. O’Donovan, Zhong Ru, Salina Parveen, Mayu O. Frank, Michael J. Moore, Robert B. Darnell
Nathalie E. Blachère, Dana E. Orange, Emily C. Gantman, Bianca D. Santomasso, Graeme C. Couture, Teresa Ramirez-Montagut, John Fak, Kevin J. O’Donovan, Zhong Ru, Salina Parveen, Mayu O. Frank, Michael J. Moore, Robert B. Darnell
View: Text | PDF
Research Article Immunology Oncology

T cells presenting viral antigens or autoantigens induce cytotoxic T cell anergy

Abstract

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.

Authors

Nathalie E. Blachère, Dana E. Orange, Emily C. Gantman, Bianca D. Santomasso, Graeme C. Couture, Teresa Ramirez-Montagut, John Fak, Kevin J. O’Donovan, Zhong Ru, Salina Parveen, Mayu O. Frank, Michael J. Moore, Robert B. Darnell

×

Figure 1

Construct and strategy for generating and validating Cdr2-KO mice.

Options: View larger image (or click on image) Download as PowerPoint
Construct and strategy for generating and validating Cdr2-KO mice. (A) S...
(A) Schematic representation of the Cdr2 locus before and after homologous recombination with the targeting vector, as well as after FLP recombination. The elements in the final targeting vector in order (5′ to 3′) were: 7.3 kb of Cdr2 intron 1 and the first 14 bp of exon 2 (shown in blue); EGFP (shown in green); an FRT site; 1.5 kb from the human GAPD gene containing its 3′UTR and 1.3 kb of 3′ flanking sequence (shown in maroon); a neomycin resistance cassette (shown in black) flanked by loxP sites; a second FRT site; and 2.3 kb of the Cdr2 gene corresponding to the 0.9 kb Cdr2 3′UTR and 1.4 kb of 3′ flanking sequence. (B) Northern blot of 13th generation Cdr2-KO and WT mouse cerebellum. RNA was hybridized with probes for Cdr2, EGFP, and the 3′UTR of Cdr2. The blot was normalized by loading equal amounts of total RNA in each lane. (C) Western blot of Cdr2-KO and WT cerebellum. Cerebellar lysates were immunoprecipitated with a paraneoplastic cerebellar degeneration patient antibody and resolved by SDS-PAGE and probed with an anti-CDR2 antibody.