Mutation of the phospholipase C-gamma1-binding site of LAT affects both positive and negative thymocyte selection

• Published in: The Journal of experimental medicine Vol. 201; no. 7; pp. 1125 - 1134
• Main Authors: Sommers, Connie L, Lee, Jan, Steiner, Kevin L, Gurson, Jordan M, Depersis, Corinne L, El-Khoury, Dalal, Fuller, Claudette L, Shores, Elizabeth W, Love, Paul E, Samelson, Lawrence E
• Format: Journal Article
• Language: English
• Published: United States 04-04-2005
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Animals; Apoptosis - immunology; Binding Sites - genetics; Calcium - metabolism; Cell Proliferation; DNA Primers; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Lymphoproliferative Disorders - genetics; Membrane Proteins - genetics; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Muscle Proteins - metabolism; Mutation - genetics; Phospholipase C gamma; Phosphoproteins - genetics; Phosphoproteins - metabolism; Receptors, Antigen, T-Cell - genetics; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction - genetics; Signal Transduction - immunology; T-Lymphocytes - immunology; T-Lymphocytes - physiology; Thymus Gland - cytology; Thymus Gland - immunology; Type C Phospholipases - metabolism
• ISSN: 0022-1007

Linker for activation of T cells (LAT) is a scaffolding adaptor protein that is critical for T cell development and function. A mutation of LAT (Y136F) that disrupts phospholipase C-gamma1 activation and subsequent calcium influx causes a partial block in T cell development and leads to a severe lymphoproliferative disease in homozygous knock-in mice. One possible contribution to the fatal disease of LAT Y136F knock-in mice could be from autoreactive T cells generated in these mice because of altered thymocyte selection. To examine the impact of the LAT Y136F mutation on thymocyte positive and negative selection, we bred this mutation onto the HY T cell receptor (TCR) transgenic, recombination activating gene-2 knockout background. Female mice with this genotype showed a severe defect in positive selection, whereas male mice exhibited a phenotype resembling positive selection (i.e., development and survival of CD8(hi) HY TCR-specific T cells) instead of negative selection. These results support the hypothesis that in non-TCR transgenic, LAT Y136F knock-in mice, altered thymocyte selection leads to the survival and proliferation of autoreactive T cells that would otherwise be negatively selected in the thymus.