Transgene-encoded human CD2 acts in a dominant negative fashion to modify thymocyte selection signals in mice.
CD2 is a cell surface glycoprotein present on all T cells which has been shown to function as an adhesion and signaling molecule. Expressed early in T cell development, human CD2 (HCD2) has been suggested to play a role during thymopoiesis. However, the relevance of CD2 in T cell development has been called into question recently, as neither disruption of the CD2 gene nor anti-CD2 antibody treatment of fetal thymic organ cultures in mouse were shown to have any discernible consequences. We have expressed HCD2 at high levels in transgenic mice and found a profound effect of the transgene on thymocyte differentiation. Transgenic thymuses are considerably reduced in cell number as a consequence of increased apoptosis of double-positive (DP) thymocytes in the cortex. The remaining DP cells have up-regulated levels of T cell receptor (TCR) and are resistant to apoptosis mediated by administration of antigen. These effects are dependent on the cytoplasmic domain of HCD2, as mice expressing comparable levels of a tailless HCD2 transgene have a normal phenotype. The HCD2 cytoplasmic domain contains several regions of identity with mouse CD2 and can interact effciently with mouse intracellular signaling machinery. These results suggest there is considerable cross-talk between CD2 and TCR on developing thymocytes with consequences for the stimulation threshold of mature T cells.
Melton
E
E
Division of Molecular Immunology, National Institute for Medical Research, London, GB.
Sarner
N
N
Torkar
M
M
van der Merwe
P A
PA
Russell
J Q
JQ
Budd
R C
RC
Mamalaki
C
C
Tolaini
M
M
Kioussis
D
D
Zamoyska
R
R
D000818:Animals; D015703:Antigens, CD / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects; D018801:CD2 Antigens / Q000235:genetics* / Q000502:physiology*; D000071178:CD48 Antigen; D017637:Clonal Deletion / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051379:Mice; D008822:Mice, Transgenic; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics*; D019061:src-Family Kinases / Q000187:drug effects
D015703:Antigens, CD; D018801:CD2 Antigens; D000071178:CD48 Antigen; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases