Synthesis Question #1: Signaling during T cell development (8 points) A. To inve
ID: 213472 • Letter: S
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Synthesis Question #1: Signaling during T cell development (8 points) A. To investigate how T-cell receptor signaling regulates T cell development in the thymus, a mutant mouse is generated with a deficiency in the T cell tyrosine kinase, LCK (Lck mice). Analysis of thymgcytes from these mice, stained with antibodies to CD4 and CD8, is shown in Figure to the right. Wild-type C04 C04 a) What is the explanation for the altered number and subsets of thymgcytes in Lck mice? (4 points) CD8 CD8 2 x 10 cells 2 x 10% cells B. Due to the defect observed in the germline Lck-deficient mice, it is not possible to use these mice to examine any potential role for this T-cell receptor signaling protein at later stages of thvmocyte development. To circumvent this CD4 problem, conditional Lck-deficient mice are generated by crossing mice with a homozygous floxed allele of Lck(Lckon to mice that express the sre recombinase in CD4'CD8 double-positive thymocytes i.e., CD4-cre). When cre is expressed at the double-positive stage, the Lck gene is deleted, and thymecytes become Lck-deficient at that time. The thvmocyte profile of these Lckx CD4-cre mice is shown in Figure to the right. Wild-type CD4 CD8 CD8 2 x 10 cells 2 x 10clls b) What is the explanation for the altered thymecyte profile seen in Lckx CD4-cre mice? (4 points)Explanation / Answer
Q.1 Lck signalling is crucial for development of CD4 and CD8 lineage in thymocytes. Lck is a molecular switch associated with Coreceptor molecules and controls lineage commitment. Lck is associated better with CD4 coreceptor molecule than CD8 coreceptor molecule. In thymocytes about 25 -50% of surface CD4 associated with Lck whereas in case of CD8 coreceptor molecules only 2% are associated with Lck. When Lck is constitutively active is will favour CD4 selection than CD8. When Lck is inactive it will favour CD8 selection.
In the given experiment in case of wild type mice as Lck is active CD4 is expressed on thymocytes surface so antibodies against CD4 can bind to CD4 coreceptors. CD8 will also present on some thymocytes at least 2% as stated above. so we can see results shown in graph of wild type mice.
In case of Lck--/-- defective mice as Lck is inactive no selection of CD4 cells will occur. So no CD4 coreceptor present on surface of thymocytes where CD4 antibody can bind. But Lck inactivation will favor CD8 selection and hence CD8 coreceptor will be present on thymocyte surface where CD8 antibodies can bind.So we can see graph as shown in Lck--/- mutant mice graph. No binding of CD4 coreceptor with CD4 antibody and binding of CD8 coreceptor With CD8 antibody due to absence of Lck is responsiblle for altered number and subsets in thymocytes.
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