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Nonclassical MHC class Ib–restricted cytotoxic T cells monitor antigen processing in the endoplasmic reticulum

Nature Immunology volume 13, pages 579–586 (2012)Cite this article

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Abstract

The aminopeptidase ERAAP is essential for trimming peptides presented by major histocompatibility complex (MHC) class I molecules. Inhibition of ERAAP by cytomegalovirus results in evasion of the immune response by this virus, and polymorphisms in ERAAP are associated with autoimmune disorders. How normal ERAAP function is monitored is unknown. We found that inhibition of ERAAP rapidly induced presentation of the peptide FYAEATPML (FL9) by the MHC class Ib molecule Qa-1b. Antigen-experienced T cells specific for the Qa-1b–FL9 complex were frequent in naive mice. Wild-type mice immunized with ERAAP-deficient cells mounted a potent CD8+ T cell response specific for Qa-1b–FL9. MHC class Ib–restricted cytolytic effector cells specifically eliminated ERAAP-deficient cells in vitro and in vivo. Thus, nonclassical Qa-1b–peptide complexes direct cytotoxic T cells to targets with defective antigen processing in the endoplasmic reticulum.

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Figure 1: Wild-type CD8+ T cells respond to pMHCIa and pMHCIb expressed by ERAAP-KO cells.
Figure 2: The gene encoding Fam49b is the source of the antigen presented by Qa-1b in the absence of ERAAP function.
Figure 3: FL9 is the naturally processed peptide presented by Qa-1b molecules.
Figure 4: The Qa-1b–FL9 complex is an immunodominant T cell ligand.
Figure 5: QFL T cells are antigen experienced in naive mice.
Figure 6: Effector and memory QFL T cells are generated in response to ERAAP-KO cells.
Figure 7: Wild-type CTLs specifically eliminate ERAAP-KO cells expressing unique pMHCIb complexes.

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Acknowledgements

We thank the Tetramer Core Facility of the US National Institutes of Health for tetramer reagents; K. Söderstrom and E. Engleman (Stanford University) for Qa-1b-deficient mice generated by H. Cantor and colleagues (Harvard University); H. Cantor (Harvard University) for lentiviral vectors expressing Qa-1b; D. King for peptide synthesis; H. Nolla for assistance with cell sorting; K.C. Lind and A.H. Bakker for discussions and comments on the manuscript; and H. Dani for technical assistance. Supported by Irvington Institute Fellowship Program of the Cancer Research Institute (N.A.N.) and the US National Institutes of Health (N.S.).

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  1. Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California, Berkeley, California, USA

    Niranjana A Nagarajan, Federico Gonzalez & Nilabh Shastri

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  1. Niranjana A Nagarajan
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N.A.N. and N.S. designed the study and wrote the manuscript; and N.A.N. and F.G. did the experiments.

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Correspondence to Nilabh Shastri.

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Nagarajan, N., Gonzalez, F. & Shastri, N. Nonclassical MHC class Ib–restricted cytotoxic T cells monitor antigen processing in the endoplasmic reticulum. Nat Immunol 13, 579–586 (2012). https://doi.org/10.1038/ni.2282

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