T Cell Development and Effector Development

What is the overall purpose of Michels's T-cell lecture?

To establish the basic framework for T-cell development, activation, migration, and effector function before applying these concepts to diseases and clinical cases;

What does Michels say this lecture is doing for later immunology material?

Setting the stage so T-cell biology can later be placed into disease and clinical contexts;

What major reference does Michels use for the lecture?

Basic Immunology by Abbas;

What does APC stand for?

Antigen-presenting cell;

What does HLA stand for?

Human leukocyte antigen;

How does Michels say HLA and MHC are often used?

They are often used interchangeably in clinical and much research language even though immunologists may distinguish them more precisely;

What does TCR stand for?

T-cell receptor;

What does CTL stand for?

Cytotoxic T lymphocyte;

What does IL indicate in cytokine names?

Interleukin;

What are the major learning areas Michels identifies for T-cell development?

Development from bone marrow to thymus, developmental checkpoints, and eventual migration to the periphery;

Where do T-cell precursors originate?

Bone marrow;

Where do T cells mature?

The thymus;

What concept does Michels repeatedly emphasize during T-cell development?

Checkpoints and checks and balances;

What two specific things must match for T-cell recognition?

The HLA molecule and the antigenic peptide;

What major activation topic does Michels emphasize?

The signals necessary for T-cell activation;

Does Michels cover superantigens in detail during this lecture?

No. She says that topic will be covered in the Wednesday BSC case setting;

Should this lecture be used as the main source for detailed superantigen mechanisms?

No. Michels explicitly defers that material to the Wednesday session;

What T-cell topics does Michels say will occupy much of the latter lecture?

CD4-positive T-cell subsets and their different functions;

Why does Michels spend more time on CD4 than CD8 subsets?

CD4 cells have multiple functional subsets whereas she presents CD8 cells as a simpler single major cytotoxic subset;

What does Michels mean by cell-mediated immunity in this lecture?

Essentially T-cell-mediated immune activity;

What are the two broad components of cell-mediated immunity covered?

Activation and differentiation of T lymphocytes followed by their effector functions;

What receptor defines a T cell?

The T-cell receptor or TCR;

What are the two major chains of the conventional TCR?

Alpha and beta;

What type of recombination generates TCR diversity?

V(D)J recombination;

Which proteins are involved in TCR gene recombination?

RAG proteins;

What region of the TCR varies among receptors?

The variable region;

How many hypervariable loops does Michels describe in the TCR variable region?

Three;

Which CDR does Michels identify as the most variable?

CDR3;

Why is CDR3 particularly variable and important?

It contacts the peptide and provides substantial antigen specificity;

What happens to the TCR after it is generated?

It remains membrane-bound;

Does a TCR undergo class switching?

No;

Does a TCR undergo affinity maturation?

No;

What three TCR features does Michels specifically group together?

Membrane-bound, no class switching, and no affinity maturation;

How does this distinguish the TCR from a B-cell immunoglobulin response?

B-cell immunoglobulins can be secreted and undergo class switching and affinity maturation while the TCR does not;

What type of TCR do most T cells express?

Alpha-beta TCR;

What less common T-cell receptor population does Michels acknowledge?

Gamma-delta T cells;

Where are gamma-delta T cells particularly found?

Epithelial compartments;

Approximately what percentage of T cells does Michels say are gamma-delta cells?

About 5–10%;

Does Michels expect detailed gamma-delta T-cell biology in this OMS1 lecture?

No. She acknowledges their existence but says she will not go into further detail for the year-one course;

What does a conventional TCR recognize?

A peptide fragment presented in the context of an MHC or HLA molecule;

Does the TCR recognize an intact free protein antigen like a BCR can?

No. Michels emphasizes recognition of peptide fragments bound to HLA;

What two components must the TCR physically recognize during antigen recognition?

The peptide and the HLA molecule;

Why is CDR3 well suited for high variability?

It contacts the peptide and therefore needs substantial sequence diversity for antigen specificity;

Approximately how many residues in an HLA-peptide complex does Michels say the TCR may recognize?

As few as 1–3 residues;

How does Michels characterize the strength of TCR binding to peptide-HLA?

Relatively weak;

What consequence follows from the weak TCR-peptide-HLA interaction?

Additional cell-surface molecules are absolutely essential for effective T-cell activation;

Is TCR binding to peptide-HLA sufficient by itself for normal naïve T-cell activation?

No;

What is HLA restriction?

A T cell must recognize both the appropriate HLA molecule and its specific peptide antigen;

What happens if the correct peptide is presented on the wrong HLA molecule?

The T cell does not recognize it;

What happens if the correct HLA molecule presents the wrong peptide?

The T cell does not recognize it;

What is the simplest Michels rule for HLA restriction?

Correct HLA + correct peptide are both required;

A TCR recognizes peptide X presented by HLA-A. Will it recognize peptide X presented by HLA-B?

Not necessarily and in Michels's example it does not because the HLA conformation is wrong;

A TCR recognizes peptide X on HLA-A. Will it recognize peptide Y on HLA-A?

No if the TCR is not specific for peptide Y;

What is the clinical concept Michels says strongly connects to HLA restriction?

Transplantation;

Why does HLA restriction matter in transplantation?

T-cell recognition depends partly on the specific HLA molecules being encountered;

What two things were required for killing in Michels's mouse example?

The appropriate MHC strain and the appropriate viral antigen;

If the viral antigen changes while MHC stays correct, what happens to recognition?

Recognition can be lost;

If MHC changes while the viral antigen stays correct, what happens to recognition?

Recognition can be lost;

What does Michels say about detailed V(D)J recombination testing?

She defers detailed V(D)J recombination teaching and testing to Dr. Towne;

Why does Michels not spend substantial time teaching V(D)J recombination?

T cells use the same general mechanism already taught by Towne for B-cell receptor diversity;

Who does Michels explicitly say will test V(D)J recombination?

Dr. Towne;

What two diversity concepts does Michels still remind students occur in TCR generation?

Combinatorial diversity and junctional diversity;

Does the body retain every theoretically possible TCR generated by recombination?

No;

What process explains why many potential TCRs are eliminated?

Positive and negative selection during thymic development;

Why eliminate TCRs that will not function effectively?

They would not contribute useful antigen recognition and would unnecessarily occupy space in the immune repertoire;

From what progenitor does T-cell development begin?

A hematopoietic stem-cell-derived progenitor;

What is the first T-cell phenotype Michels emphasizes?

Double negative;

What does double negative mean?

The developing T cell expresses neither CD4 nor CD8;

What is the phenotype of a double-negative T cell?

CD4− CD8−;

What general marker does Michels say all T cells possess?

CD3;

What two markers distinguish major conventional T-cell lineages?

CD4 and CD8;

What receptor checkpoint develops after the double-negative stage?

The pre-T-cell receptor;

What stage follows the early pre-T-cell stage?

Double-positive;

What does double positive mean?

The thymocyte expresses both CD4 and CD8;

What is the phenotype of a double-positive thymocyte?

CD4+ CD8+;

What happens to the double-positive thymocyte?

It is tested for its interactions with self-MHC and self-peptide;

Where does this developmental testing occur?

The thymus;

What happens when a developing T cell weakly recognizes MHC class II plus peptide?

It undergoes positive selection toward a mature CD4-positive T cell;

Which HLA class goes with CD4?

Class II;

What happens when a developing T cell weakly recognizes MHC class I plus peptide?

It undergoes positive selection toward a mature CD8-positive T cell;

Which HLA class goes with CD8?

Class I;

What level of MHC recognition is desirable during positive selection?

Weak recognition;

Why does Michels say some weak recognition of self-MHC is necessary?

A mature T cell must be capable of recognizing antigen when it is later presented by the body's own MHC molecules;

What happens if a thymocyte has no recognition of MHC-peptide?

It fails to develop and dies by apoptosis;

Why is a T cell that cannot recognize self-MHC useless in the periphery?

It would not recognize antigens presented by the body's APCs;

What happens if a thymocyte recognizes self-MHC plus self-peptide too strongly?

It dies by apoptosis through negative selection;

What is the major purpose of negative selection?

Elimination of strongly autoreactive T cells;

Why are strongly self-reactive T cells dangerous?

They could attack the body's own tissues and contribute to autoimmune disease;

What can happen clinically when negative selection fails?

Autoreactive T cells may escape and contribute to clusters of autoimmune disease;

What is the simplest three-outcome rule for thymic selection?

No recognition dies, weak recognition survives, strong recognition dies;

Which selection process retains useful T cells?

Positive selection;

Which selection process eliminates strongly autoreactive T cells?

Negative selection;

Where does Michels describe early T-cell development beginning within the thymus?

The cortex;

What type of thymic cells interact with developing T cells during cortical development?

Thymic epithelial cells;

Where does later self-reactivity testing occur?

The thymic medulla;

What cells does Michels emphasize in the medulla for later selection?

Medullary thymic epithelial cells;

What happens after positive selection?

The cell becomes single positive for either CD4 or CD8;

What does single positive mean?

The mature thymocyte expresses either CD4 or CD8 rather than both;

What happens to a successfully selected T cell after thymic development?

It leaves the thymus as a mature naïve T cell;

Does naïve mean immature?

No. A naïve T cell is mature but has not yet been activated by its specific antigen;