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
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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

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Figure 3

T cell expression of CDR2 is sufficient to confer tolerance.

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T cell expression of CDR2 is sufficient to confer tolerance. IFN-γ ELISP...
IFN-γ ELISPOTs of CD8+ T cells from bone marrow (BM) chimera mice 14 days after immunization with adenovirus expressing CDR2 (AdV-CDR2) and cultured with RMA-S cells pulsed with either OVA or CDR2-120 peptide immediately ex vivo (A) and after 7 days of splenocyte in vitro stimulation (B). Each triangle represents the mean of triplicate wells and the bar with error bars represents the mean and standard deviations of mice in that group. These data are representative of 2 experiments. KO→KO indicates Cdr2-KO BM donor cells transplanted into Cdr2-KO host mice (n = 1), KO→WT (n = 4) indicates Cdr2-KO BM donor cells transplanted into WT host mice, and WT→KO (n = 4) indicates WT BM donor cells transplanted into Cdr2-KO host mice. (C) Flow cytometry of hematopoietic cells from WT or Cdr2-KO mice. The EGFP gene replaces the Cdr2 gene in Cdr2-KO mice. Gray filled = WT, blue line = Cdr2-KO. One experiment is shown and is representative of 5 experiments. (D) BM chimeras were established as in A and B with the addition of RAG/Cdr2-KO→WT (n = 3) indicating a mix of 50:50 Rag1-KO and Cdr2-KO BM cells transplanted into WT mice. Fourteen days after immunization, splenocytes were stimulated in vitro for 7 days with CDR2-120 peptide and CD8+ T cells were tested for response to RMA-S cells pulsed with either OVA or CDR2-120 peptide by IFN-γ ELISPOT in triplicate wells. Results presented are 1 of 2 experiments. Each triangle represents the mean of triplicate wells and the bar with error bars represents the mean and standard deviations of mice in that group. These data are representative of 2 experiments. KO→KO (n = 3), WT→WT (n = 5), RAG/KO→WT (n = 3). *P < 0.05, **P < 0.01, ***P < 0.001; ns, statistically not significant as calculated using unpaired Student’s t test. SFC, spot-forming cells; OVA, ovalbumin peptide.