What are the tenets of clonal selection theory?

Each lymphocyte has a unique receptor, receptors are made before infection, antigen selects the matching cell, the cell proliferates, clones become effector and memory cells, and self-reactive cells are eliminated

Why is clonal selection theory relevant?

Explains specificity, immune memory, and how vaccines work

What is the difference between stem cells and stromal cells?

Stem cells become immune cells, stromal cells support development

How do stromal cells support development?

Through physical contact and soluble factors (cytokines)

What are examples of stromal support?

SCF–Kit (contact) and IL-7 (cytokine)

What happens in the Pro-B cell stage?

Heavy chain rearrangement

What happens in the Pre-B cell stage?

Heavy chain made, pre-BCR forms, proliferation

What happens in the immature B cell stage?

Light chain rearrangement and IgM expression

What happens in the mature naïve B cell stage?

IgM and IgD expression, leaves bone marrow

What is a pre-B cell receptor?

A test receptor for the heavy chain

What is the purpose of the surrogate light chain?

Tests if the heavy chain works

What are the surrogate light chains?

VpreB and λ5

How is the heavy chain tested?

Forms pre-BCR with surrogate light chain and must signal

What is a productive rearrangement?

Functional receptor with correct reading frame and no stop codon

What is a non-productive rearrangement?

Nonfunctional receptor due to frameshift or stop codon

What determines if rearrangement is productive?

In-frame sequence, no stop codon, full protein

What is the relationship between rearrangement and allelic exclusion?

Productive rearrangement stops the other allele; non-productive leads to trying the second allele

What is the difference between heavy and light chain rearrangement?

Heavy chain has one chance; light chain can retry and edit

What are the checkpoints of B cell development?

Heavy chain checkpoint, light chain checkpoint, self-tolerance checkpoint

What proteins are expressed early in B cell development?

CD19 and IL-7 receptor

What proteins are expressed mid-development?

Pre-BCR

What proteins are expressed later?

IgM and IgD

How does the heavy chain variable region attach to the constant region?

By RNA splicing

What is recombination vs splicing?

Recombination is DNA-level VDJ joining; splicing is RNA-level joining to constant region

Why is the order of constant regions important?

Determines antibody class

What is the role of alternative splicing?

Allows IgM and IgD expression

What happens during negative selection of B cells?

Self-reactive cells undergo apoptosis, anergy, or receptor editing

What is apoptosis?

Programmed cell death

What is anergy?

Cell becomes inactive

What is receptor editing?

Light chain is changed to avoid self-reactivity

Why can receptor editing only occur in light chains?

Heavy chain rearrangement is complete and cannot be redone

What is central tolerance?

Removal of self-reactive cells in bone marrow

What is peripheral tolerance?

Control of self-reactive cells outside bone marrow

Why is peripheral tolerance needed?

Not all self-antigens are in bone marrow

What are B1 and marginal zone B cells?

Innate-like, fast responders

What are B2 cells?

Conventional adaptive B cells

Where does T cell development begin and end?

Begins in bone marrow, ends in thymus

What is a thymocyte?

Developing T cell

What is the difference between cells entering and leaving thymus?

Entering are immature; leaving are CD4 or CD8 mature cells

What is the role of the Notch receptor?

Drives T cell development

What happens to the thymus over time?

Shrinks after puberty (involution)

What are the regions of the thymus?

Cortex and medulla

What happens in the cortex?

Positive selection

What happens in the medulla?

Negative selection

What are the stages of T cell development?

DN → DP → SP

How long does T cell development take?

About 2–3 weeks

What does the CD4

CD8 flow plot show? / None → both → one

What does the CD44

CD25 flow plot show? / 44 → both → 25 → none

What are double negative cells?

No CD4 or CD8

What are double positive cells?

Both CD4 and CD8

What are DN1 cells?

Earliest stage, entry into thymus

What happens in DN2 cells?

TCR rearrangement begins

What happens in DN3 cells?

β chain rearrangement and pre-TCR checkpoint

What happens in DN4 cells?

Proliferation and CD4/CD8 expression

What are αβ T cells?

Most common, adaptive

What are γδ T cells?

Less common, innate-like

What is the pre-TCR made of?

β chain + pTα + CD3

What is β-selection?

Checkpoint testing β chain function

What is positive selection?

Keeps T cells that recognize self-MHC

What is self-restriction?

T cells must recognize antigen with self-MHC

What is the goldilocks model?

Binding must be just right

What happens with weak binding?

Death by neglect

What happens with strong binding?

Apoptosis

What happens with intermediate binding?

Survival

What happens with slightly high affinity?

Treg formation

What is lineage commitment?

Becoming CD4 or CD8 T cell

What determines CD4 vs CD8?

Type of MHC recognized

What is negative selection?

Removal of self-reactive T cells

What is self-tolerance?

Immune system ignores self

What are mechanisms of negative selection?

Apoptosis, anergy, Treg formation

What is AIRE?

Protein that presents self-antigens in thymus

What is positive selection characterized by?

Cortex location, self-MHC recognition, ~5% survival

What is negative selection characterized by?

Medulla location, removal of self-reactive cells