Janeway Immunobiology Ch. 8: B and T Lymphocyte Dev

Describe the roles of CXCL12 and Interleukin-7 (IL-7) in early B cell development within the bone marrow.

Explain the significance of RAG-1 and RAG-2 enzymes in B cell development, and at what specific stage of B cell development are these enzymes most active?

What is the role of the surrogate light chain in B cell development, and why is its co-expression with the rearranged heavy chain important?

Describe the signaling mechanism initiated by the crosslinking of the heavy chain by the surrogate light chain, and explain why this signaling is critical for B cell survival.

Explain how nonproductive light chain rearrangements can be rescued during B cell development, and what advantage this rescue mechanism provides to the developing B cell.

Describe the role of stromal cells in B-cell development within the bone marrow. What specific functions do these cells perform, and how do they contribute to the differentiation and survival of B-cell progenitors?

Explain the concept of positive selection in T-cell development. What is being 'selected' and what happens to T-cells that fail to be positively selected?

Describe the process of negative selection in T-cell development. What potential problem does this process address, and how does it contribute to immune tolerance?

Compare and contrast the roles of the bone marrow and the thymus in lymphocyte development. What specific cell types develop in each location, and what critical processes occur in each environment?

Explain how successful rearrangement of the heavy and light chain genes in B-cells (or alpha and beta in T-cells) influences their survival and further development. What happens to cells that fail to successfully rearrange these genes?

How does DiGeorge's syndrome impact the adaptive immune system, and what specific developmental failure leads to this outcome?

Explain the dual role of the thymus in T cell development, emphasizing the opposing selection pressures applied to developing T cells.

Describe how mutations in the Foxn1 transcription factor affect both the physical development and adaptive immunity in nude mice.

What are the key cellular components found in the cortex and medulla of the thymus, and how do their functions differ in T cell development?

Explain what occurs during T cell receptor rearrangement and why this process is crucial for adaptive immunity.

Contrast the roles of cortical and medullary epithelial cells in T cell education within the thymus.

Describe the significance of secondary lymphoid organs (SLOs) in the context of mature T cell function.

Describe the potential outcomes for immature B cells that bind to self-molecules within the bone marrow during central tolerance.

What is anergy in the context of B cell tolerance, and how does it contribute to preventing autoimmunity?

Explain the fate of immature (transitional) B cells that bind abundant, multivalent self-antigens shortly after emigrating to the periphery.

How does the binding of low-affinity, non-crosslinking self-antigens affect immature B cells in the periphery?

Outline the key difference between immature (transitional) B cells and mature B cells in terms of their response to antigen.

Describe the two locations where B cell tolerance mechanisms primarily operate, and briefly explain what occurs in each.

Detail the sequential steps in B cell development, starting from their origin in the bone marrow to their activation in peripheral lymphoid organs.

Compare and contrast central and peripheral B cell tolerance mechanisms, highlighting how they complement each other to prevent autoimmunity?

Mature T cells are activated by binding to MHC or self-peptides presented on MHC.

Immature thymocytes proliferate in the medulla prior to starting T cell receptor rearrangement.

Approximately 2% of all thymocytes survive to become mature T cells.

Rearrangement of the T cell receptor α chain starts in the double-negative stage (DN2).

Thymocytes upregulate both CD4 and CD8, transitioning into the double-positive stage, after successful rearrangement of the alpha chain.

Thymocytes enter positive and negative selection before they express a complete T cell receptor.

Progenitor cells arrive in the thymus at the cortex.

During thymic selection, a double-positive thymocyte becomes either CD4+ (MHCI-restricted) or CD8+ (MHCII-restricted).

One goal of T cell selection is to ensure T cells are autoreactive.

During thymocyte differentiation, failure to properly rearrange the T cell receptor genes invariably leads to apoptosis.

T cell receptor rearrangement in the thymus involves the precise and sequential recombination of V, D, and J gene segments in both the α and β chains, ensuring a diverse but non-random repertoire.

Positive selection in the thymus ensures that T cells can recognize self-antigens presented by MHC molecules, preventing autoimmune reactions in the periphery.

Negative selection of T cells in the thymus is primarily mediated by dendritic cells and macrophages, which present self-antigens to developing thymocytes with abnormally high affinity, triggering apoptosis.

Mature T cells, having successfully navigated positive and negative selection, express both CD4 and CD8 co-receptors, enabling them to interact both with MHC class I and MHC class II molecules on antigen-presenting cells.

Anergic B cells, unlike ignorant B cells, express high-affinity self-antigen receptors, rendering them highly sensitive to crosslinking and subsequent activation upon encountering even low concentrations of self-antigens in the periphery.

Mature B cells, having passed the transitional stage, are characterized by their inability to undergo apoptosis upon encountering abundant soluble self-antigens, allowing them to persist indefinitely in the periphery, regardless of self-reactivity.

In DiGeorge's syndrome, the failure of the thymic epithelium to develop normally leads to an overproduction of mature T cells, enhancing immune responses.

The primary function of the thymus is to facilitate T cell education, a process that ensures T cells can effectively bind to Major Histocompatibility Complex (MHC) molecules and respond to self-antigens.

T cell receptor rearrangement occurs exclusively in the secondary lymphoid organs (SLOs), where mature T cells are activated by antigens encountered during immune responses.

The cortex of the thymus primarily houses maturing thymocytes, dendritic cells, and phagocytic cells, critical for the later stages of T cell development and selection.

Nude mice, characterized by mutations in the Foxn1 transcription factor, exhibit enhanced thymus development and adaptive immunity due to the absence of terminal epithelial differentiation.

During T cell development in the thymus, the processes of positive and negative selection ensure that T cells are autoreactive, effectively targeting and eliminating self-antigens to maintain immune homeostasis.

Thymic epithelial cells function merely as structural components within the thymus, providing a scaffold for developing thymocytes without actively participating in T cell selection processes.

The primary role of Hassall's corpuscles, found in the thymic cortex, is to facilitate the initial stages of T cell receptor rearrangement by providing a specialized microenvironment.

In T cell development, the processes of gene rearrangement, cell-surface protein expression, signaling protein activation, and transcription factor regulation are entirely independent of each other, ensuring greater diversity in the T cell repertoire.

Central Lymphoid Organs

Peripheral Lymphoid Organs

Bone Marrow

Thymus

Stromal Cells

CXCL12

Interleukin-7 and Stem Cell Factor (SCF)

RAG-1/-2 Enzymes

Productively Rearranged Immunoglobulin Gene

VpreB Protein

Central B cell Tolerance

Self-Molecule Binding Outcome

Anergy

Peripheral B cell Tolerance

Immature (Transitional) B Cells

Fate of Immature B Cells & Abundant Self-Antigens

Mature B Cells

B Cell Development Summary

T Cell Receptor Rearrangement

T Cell Migration to SLOs

Thymus Organization

Thymic Epithelial Network

DiGeorge's Syndrome

Nude Mice (Thymus)

Goals of Thymic Education

Apoptosis of Autoreactive B Cells

Self-Molecule Binding Fate

Anergy Induction

B Cell Activation

SLOs (T cell activation)

Thymus Cortex

Thymus Medulla

DiGeorge's Syndrome (Thymus)

Nude Mice (Foxn1)

Thymic Education Goals

MHC Restriction (T cells)

Non-Autoreactive T Cells

Hassall's Corpuscles (Thymus)

Double-Negative (DN) Thymocytes

Double-Positive (DP) Thymocytes

Single-Positive (SP) Thymocytes

Positive Selection (T cells)

Negative Selection (T cells)

MHC Restriction

T Cell Tolerance

DN2 Stage