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Apoptosis of a T cell population following cross‐linking of CD8
Author(s) -
Thiemann Sandra,
Potter Terry A
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.359
Subject(s) - cd8 , thymocyte , mhc class i , major histocompatibility complex , t cell receptor , microbiology and biotechnology , biology , t cell , cytotoxic t cell , cd3 , mhc class ii , immune system , immunology , biochemistry , in vitro
The binding affinity of CD8 for Major Histocompatibility Complex class I (MHC class I) molecules changes during thymocyte and T cell differentiation. A proportion of CD8 molecules that are expressed on double‐positive (DP, CD4+CD8+) thymocytes and activated mature T cells are not sialylated and have a high affinity for MHC class I molecules. Previous work in our laboratory on thymocyte death showed that a proportion of DP thymocytes die upon CD8‐cross‐linking with either antibody to CD8 or beads coated with MHC class I molecules (Grebe KM et al. 2004. PNAS 101:10410‐10415). We hypothesize that at least some of the thymocytes that do not satisfy the criteria for positive selection die “by instruction” following cross‐linking of CD8 by MHC class I molecules. However, if the cells are positively selected and differentiate further, they do survive. The critical step in this process is the engagement of the T cell receptor and CD8 by self‐MHC class I plus peptide. The objective of this study is to investigate the effect of CD8 cross‐linking alone or CD8 and CD3/T cell receptor (TCR) cross‐linking on DP thymocytes from mice where positive selection is ablated (TCRalpha−/−; MHC−/−). Our data show that cross‐linking of CD8 leads to apoptosis while co‐engagement of CD3/TCR inhibits cell death at the very early time‐points that we examine. This very first step of thymocyte positive selection does not require new protein synthesis and critically depends on the activation of PKC, the MAPK pathway and the PI3K/AKT pathway. We will provide data examining the effects on DP thymocyte survival and death when these different survival pathways are either activated or inhibited. Evidence for the differential regulation of pro‐apoptotic proteins (such as the Bcl‐2 family member BAD) and IAPs (inhibitor of apoptosis proteins) through PKC, MAPK and the PI3K/AKT pathway will be shown.