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Cytolytic granzyme-B binding mannose-6-phophate receptor controls T cell contraction

Significance Statement

CD8 T cells which exist in lower frequencies in naive hosts are the key players in protective immunity. After proliferation in response to antigen, contraction phase begins in which a subpopulation of antigen specific T cells forms memory cell pool. This immunological memory is the basis for vaccination, and wholesome efforts have been put to improve vaccine design through manipulating T cell responses which would maximize memory T cell formation. Here the authors demonstrated for the first time that mannose-6-phosphate receptor  down-regulation has a critical role in CD8(+) T cell survival. The results of this study has implications in designing improved vaccines for variety of diseases and infections.

 

Journal Reference

Differential expression of mannose-6-phosphate receptor regulates T cell contraction

J Leukoc Biol. 2015;98(3):313-8.

Ahmed KA1, Wang L1, Griebel P1, Mousseau DD1, Xiang J2.

Show Affiliations
  1. 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.
  2. 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 [email protected]

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 cellcontraction phase, yet the mechanism that triggers apoptotic T cell death remains elusive. This study tested the hypothesis that differential cell-surface expression of mannose-6-phosphate receptor, 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 mannose-6-phosphate receptor -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 mannose-6-phosphate receptor  down-regulation has a critical role in CD8(+) T cell survival, and our findings have implications for efficient vaccine design and immunotherapy.

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