title: Differential expression of mannose-6-phosphate receptor regulates T cell contraction.
abstract: CD8(+) T cells provide protection against pathogens and cancer. After encountering a pathogenic antigen, CD8(+) T cells undergo a triphasic program of rapid proliferation, contraction, and memory formation. Most (∼90-95%) CD8(+) T cells die after vigorous proliferation in the T cell contraction phase, yet the mechanism that triggers apoptotic T cell death remains elusive. This study tested the hypothesis that differential cell-surface expression of M6PR, a multifunctional receptor that regulates lysozyme biogenesis, but also uptakes apoptosis-inducing serine-protease Gzm-B, critically determines life vs. death decisions in T cells. We demonstrate that M6PR-expression on CD8(+) T cell surfaces is dynamically regulated during LmOVA bacterial infection. Notably, time-lapse, confocal microscopy and flow cytometry confirms that M6PR(low) effectors, but not M6PR(high) effectors, escape Gzm-B lethal-hit derived from CD4(+)25(+) Treg cells. Adoptive cotransfer of M6PR(low) effectors and M6PR(high) effectors sorted from LmOVA-infected, congenic mice at the peak of CD8(+) T cell response, reveals that M6PR(low) effectors with the CD8(+) T cell memory precursor phenotype preferentially survive the CD8(+) T cell contraction and differentiate into functional, long-lasting memory CD8(+) T cells. Taken together, our data provide the first evidence, to our knowledge, that selective M6PR down-regulation has a critical role in CD8(+) T cell survival, and our findings have implications for efficient vaccine design and immunotherapy.
authors.affiliation: *Cancer Cluster, Saskatchewan Cancer Agency, Department of Oncology, Vaccine and Infectious Disease Organization - International Vaccine Centre, and Department of Psychiatry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Khawaja Ashfaque
authors.initials: KA
authors.lastname: Ahmed
authors.affiliation: *Cancer Cluster, Saskatchewan Cancer Agency, Department of Oncology, Vaccine and Infectious Disease Organization - International Vaccine Centre, and Department of Psychiatry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.affiliation: *Cancer Cluster, Saskatchewan Cancer Agency, Department of Oncology, Vaccine and Infectious Disease Organization - International Vaccine Centre, and Department of Psychiatry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Philip
authors.initials: P
authors.lastname: Griebel
authors.affiliation: *Cancer Cluster, Saskatchewan Cancer Agency, Department of Oncology, Vaccine and Infectious Disease Organization - International Vaccine Centre, and Department of Psychiatry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
authors.forename: Darrell D
authors.initials: DD
authors.lastname: Mousseau
authors.affiliation: *Cancer Cluster, Saskatchewan Cancer Agency, Department of Oncology, Vaccine and Infectious Disease Organization - International Vaccine Centre, and Department of Psychiatry, University of Saskatchewan, Saskatoon, Saskatchewan, Canada jim.xiang@usask.ca.
authors.forename: Jim
authors.initials: J
authors.lastname: Xiang
mesh_terms: D000818:Animals; D017209:Apoptosis; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D008089:Listeria monocytogenes / Q000276:immunology; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000276:immunology; D054353:Perforin / Q000378:metabolism; D017527:Receptor, IGF Type 2 / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000378:metabolism*
chemical_list: D017527:Receptor, IGF Type 2; D054353:Perforin; D010047:Ovalbumin; D053804:Granzymes