Short Answer part 1. 1. What is Notch1, including where it is expressed, and how

Question

Short Answer part 1.

1. What is Notch1, including where it is expressed, and how does the interaction between Notch1 and its ligand mediate T cell development?

2. In what way the thymic conditions is advantageous for the purposes of negative selection?

3. The surrogate light chain operating during pre-B cell development is made up of VpreB:lambda5. Its expression with mu on the pre-B cell surface is an important checkpoint in B cell maturation. Name the T cell analog of VpreB:lambda5 and discuss how it is functionally similar.

4. Mature B cells undergo somatic hypermutation after activation, which, after affinity maturation, results in the production of antibody with a higher affinity for antigen than in the primary antibody response. Suggest some reasons why T cells have not evolved the same capacity.

5. As we age, our thymus shrinks, or atrophies, by a process called involution, yet T cell immunity is still functional in old age. How do T cell numbers in the periphery remain constant in the absence of continual replenishment from the thymus and how does this differ from the maintenance of the B cell repertoire?

Explanation / Answer

Ans 1) Notch1 is basically a human gene which encodes a single pass transmembrane protein. All the proteins from the Notch family have a structural similarity that includes an extracellular domain and it also consists of multiple EGF (Epidermal growth factor-like) repeats. It is an important protein which helps in the signaling pathways. The Notch signaling pathway helps with the cell fate specification and helps in regulating the cell proliferation, differentiation and apoptosis of cells. When the Notch1 binds to its ligand, it also leads to the T-cell development. The Notch signaling helps with the T-cell development by converting the HSC (hematopoietic stem cell) derived progenitors through the thymus into the T-cell lineage. It is basically a cell surface receptors where the thymocytes interacts with the transmembrane ligands on the thymic epithelial cells. This keeps the thymocyetes into the T-cell differentiation pathway and helps in formation of T-cells.

Ans 2) The thymic situation is advantageous for negative selection as by generation of more comprehensive reserve of self peptides in the thymus, it leads to increase in the types of autorective T-cells. The autoreactive T-cells are removed from the peripheral T-cells reserve during the negative selection.

Ans 3) The analog in the developing T-cells is preTalpha which is a protein. This basically combines with the T-cell receptor Beta Chain and forms the pre Tcells receptor. The immunoglobulin heavy chain contains the V,D and J segments, pTa(alpha) are involved in binding CD3 and other components to this complex. The assembly of the overall complex helps in inducing the T-cell proliferation and leads to cessation of the rearrangement of the TCRB loci.

Ans 4) The Memory B-cells express higher level of MHC Class II molecules and this helps in the somatic hypermutation after activation. It does not involve the T-cells as there are no MHC Class II molecules which are added or involved.

Ans 5) The T-cell number remain constant even after absence of continual replenishment of thymus because after thymic atrophy, there is self renewal of the cells by cell division which makes them long lived. The B-cells are generally short lived and is the major difference. They are replenished from immature precursors derived from bone marrow and hence the balance is maintained.

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