Loss of Ly-6A.2 expression on immature developing T cells in the thymus is necessary for their normal growth and generation of the Vbeta T-cell repertoire.
Stage-specific expression of a number of cell-surface and signaling proteins is critical for normal development of T cells in the thymus. Equally important may be the loss of expression/signaling of developmentally regulated proteins for proper transitioning of developing T cells into thymic subsets. Ly-6A.2 exhibits a regulated pattern of expression on T cells maturing in the thymus, and dysregulating its expression results in arrest of developing T cells within the CD3-CD4-CD8- triple negative (TN) stage where the normal expression of Ly-6A.2 is extinguished. To further characterize the mechanisms underlying this block, we examined whether cell signaling and/or cell adhesion properties of the Ly-6A.2 molecule influenced the block in T-cell development. Analysis of bone marrow chimeras generated by injecting CFSE-labeled Ly-6A.2 transgenic bone marrow cells into irradiated syngeneic non-transgenic mice revealed normal trafficking of developing T cells from the cortex into the medulla. Production of LAT but not p56lck was diminished in CD4-CD8- DN cells from Ly-6A.2 dysregulated mice when compared with control littermates. Dysregulated expression of Ly-6A.2 did not suppress endogenous TCR-Vbeta expression. Finally, dysregulated expression of Ly-6A.2 enhanced apoptosis of an immature CD4+CD8+ (DP) subset of developing cells and altered the selected TCR-Vbeta repertoire. Taken together, these observations indicate that the termination of Ly-6A.2 expression and signaling within the CD4-CD8-CD3- subset of developing T cells is an important checkpoint during normal thymic development.
Henderson
S C
SC
Department of Cellular Biology, University of Georgia, Athens, GA, USA.
Bamezai
A
A
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000950:Antigens, Ly / Q000096:biosynthesis / Q000235:genetics*; D017209:Apoptosis / Q000502:physiology; D015704:CD4 Antigens / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D007150:Immunohistochemistry; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010750:Phosphoproteins / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D013950:Thymus Gland / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D000950:Antigens, Ly; D015704:CD4 Antigens; D002352:Carrier Proteins; C491734:Lat protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)