Exam 8: Development and Survival of Lymphocytes

T cell development in the thymus shares some similarities to a pipeline. As new progenitor cells enter the thymus, the most mature thymocytes are pushed out of the thymus to enter the circulation by a passive process.

In different mammalian species, the ratio of B cells expressing $\kappa$ versus $\lambda$ light chain-containing antibodies is about 65%:35%. In other species, such as mice, this ratio is vastly different, at 95%:5%. If a routine blood test performed on an individual revealed that their $\lambda$ -expressing versus $\lambda$ -expressing B cells were seen at a ratio of 95%:5%, this would likely indicate that the individual had:

B cell development in the bone marrow is an inherently wasteful process. Nearly half of the pro-B cells produced will die without progressing on to the next stage of B cell development. This massive loss of pro-B cells is due to:

An infant is admitted to the hospital with a history of recurrent and persistent bacterial infections. His physician suspects he has an immunodeficiency disease, and obtains a sample of the patient's peripheral blood. The white blood cells are analyzed by antibody staining followed by flow cytometry, and the results are shown in Figure. To determine the origin of the peripheral blood cell defect, a bone marrow biopsy is taken from the patient and compared to a healthy control, as shown in Figure. To obtain additional information, bone marrow cells are treated with a chemical that permeabilizes the cell membrane, allowing antibodies to enter the cells and bind to their target antigens within the cells, a technique known as ‘intracellular staining’. The results of this analysis are shown in Figure . a) What are populations 1, 2, and 3 in Figure? b) In the analysis of cell surface expression (non-permeabilized bone marrow cells), what are the IgM^lo Igκ⁺λ^neg cells as indicated by the arrow in Figure? c) What is the most likely defect causing the patient's immunodeficiency? The results shown above indicate a specific defect in B cell development. To help identify the defective or missing protein in the patient's developing B cells, bone marrow cells are isolated and protein lysates are prepared for immunoblotting. A series of antibodies are tested and the results are shown in Figure. d) Given the results from the immunoblotting experiments, what is the most likely candidate molecule (or type of molecule) responsible for the patient's immunodeficiency disease?

While many cell types in the thymus are able to induce negative selection of developing self-reactive thymocytes, bone marrow-derived antigen-presenting cells, such as macrophages and dendritic cells, appear to be the most important for this process. One likely reason for the prominent role of bone marrow-derived antigen-presenting cells in inducing negative selection of developing thymocytes is:

One feature of $\gamma$ : $\delta$ T cells that identifies them as innate, rather than adaptive, lymphocytes is their ability to produce effector cytokines within hours of initial activation.

A wild-type mouse that is heterozygous for two immunoglobulin heavy chain alleles (IgH^a/b) generates the population of B cells shown on the left of Figure . A mouse strain, also IgH^a/b, carries an inactivating mutation in the VpreB gene. In addition to producing fewer mature B cells than the wild-type mice, the VpreB-deficient mice generate B cells as shown on the right. What is the explanation of the difference seen between the wild-type and the VpreB-mutant B cells?

A key step in the development of B cells is the expression of the RAG-1 and RAG-2 recombinase proteins. The up-regulation of RAG-1 and RAG-2 in early pro-B cells is induced by:

The mouse thymus normally contains about 1–2 x 108 thymocytes, the vast majority of which are CD4+CD8+ (double-positive) cells. When thymocytes from mice with a gene deficiency in the TCR $\alpha$ locus are compared with those from TCR $\beta$ -deficient mice, a striking difference between the two different knockout lines is observed, as shown in Figure in a simplified version of flow cytometry data. The numbers of thymocytes in each thymus is indicated below the plots. -Which region of the thymus organ would show a dearth of developing thymocytes in the TCR $\alpha$ ^-/- thymus? Which region in the TCR $\beta$ ^-/- thymus?

Proteins found in the circulation travel throughout the body, including the thymus. One example is serum albumin. Developing T cells with T-cell receptors specific for peptides of human serum albumin bound to MHC class II molecules would likely be:

Marginal zone B cells are thought to represent a lineage of cells important in rapid responses to blood-borne antigens. What are the two characteristics of these cells that indicate this function?

Current evidence indicates that >95% of the CD4⁺CD8⁺ double-positive thymocytes generated will die in the thymus, and will never develop into mature CD4 or CD8 T cells. While a small proportion of these double-positive thymocytes may fail to produce a functional $\alpha$ : $\beta$ T-cell receptor, the majority of them do express a T-cell receptor complex on their surface. For any given double-positive thymocyte undergoing cell death in the thymus, what are the two possible explanations for its failure to mature?

Progenitor cells that migrate from the bone marrow to the thymus are not yet committed to the T cell lineage. T cell lineage commitment occurs as a result of signals received by the progenitor cell from thymic epithelial cells.

Experiments performed with T-cell receptor transgenic mice identified the fate of developing thymocytes that failed positive selection. Based on these findings, examination of thymocytes in MHC class I-MHC class II-deficient mice (lacking all MHC class I and class II expression in the thymus) would show:

The thymic cortex has a substantial population of macrophages in addition to the developing T cells (i.e., thymocytes). These macrophages are extremely useful in:

Unlike $\alpha$ : $\beta$ T cells, $\gamma$ : $\delta$ T cells are considered to be components of the innate immune system. One feature of $\gamma$ : $\delta$ T cells that leads to their classification as innate cells is:

Autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are characterized by high levels of circulating autoreactive antibodies in the patient's circulation. An analysis of developing B cells in the bone marrow of these individuals might reveal that in some cases: