Adaptive Immunity and T Cell Receptors

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Questions and Answers

What is the function of adaptive immune receptors?

To provide immediate defense against pathogens

To enhance the speed of the primary immune response

To produce antibodies in response to any pathogen

To recognize pathogens and initiate adaptive immune responses (correct)

Which type of cell is primarily responsible for the adaptive immune response?

Monocytes

Natural killer cells

Macrophages

B cells (correct)

The secondary immune response is characterized by which of the following?

A weaker response than the primary immune response

An absence of immune memory

A faster and stronger response than the primary immune response (correct)

A slower activation compared to the primary response

Which statement about self-reactive T and B cells is true?

Self-reactive T cells are deleted in the thymus Signup and view all the answers

Which chains are most commonly found in T cell receptors?

Alpha and beta Signup and view all the answers

How many diversity (D) exons do TCR alpha genes have?

0 Signup and view all the answers

In which anatomical structure do immature T cells undergo receptor rearrangement?

Thymus Signup and view all the answers

What represents the most diverse segment of TCR beta chains?

Variable (V) Signup and view all the answers

What is the primary purpose of TCR rearrangement in thymocytes?

To generate diversity in T cell receptors Signup and view all the answers

During positive selection, what must a TCR be able to do?

Bind self MHC with low affinity Signup and view all the answers

What happens to T cells that bind self MHC with high affinity during negative selection?

They undergo apoptosis Signup and view all the answers

What is the estimated diversity of the T cell receptor repertoire?

10^16 - 10^18 unique TCRs Signup and view all the answers

What proportion of thymocytes typically survives the selection process?

5% Signup and view all the answers

What occurs after T cells express TCRs that can recognize antigen?

They are prepared to detect invading pathogens Signup and view all the answers

Which stage is characterized by random rearrangement of TCRs in thymocytes?

Subcapsular region of the thymus Signup and view all the answers

What do survivorship signals during positive selection indicate about a TCR?

It can bind self MHC with compatible affinity Signup and view all the answers

What does a mismatch in haplotypes indicate regarding T cell recognition?

T cells will not recognize the antigen. Signup and view all the answers

Which type of T cells does MHC class I present to?

CD8+ T cells Signup and view all the answers

What is responsible for the degradation of intracellular proteins into peptides?

Proteasome Signup and view all the answers

What induces the expression of the immunoproteasome in certain cells?

Interferon-gamma Signup and view all the answers

What characteristic do peptides presented by MHC class I generally have?

They are around 8-10 amino acids long with a hydrophobic or basic C-terminus. Signup and view all the answers

What is the main reason individuals are attracted to others with different MHC haplotypes?

Different haplotypes allow for a better immune response. Signup and view all the answers

What advantage do heterozygotes have over homozygotes in antigen presentation?

Heterozygotes present a larger repertoire of antigens. Signup and view all the answers

How does the degree of relatedness between haplotypes affect antigen binding?

More closely related haplotypes bind more antigens than monozygotes. Signup and view all the answers

Which statement regarding allelic advantage in HIV progression is correct?

Certain HLA alleles provide a slower progression of HIV disease. Signup and view all the answers

What process occurs in the thymus to help T cells recognize self-MHC?

Positive selection allows T cells that recognize self-MHC with moderate affinity to survive. Signup and view all the answers

What is meant by MHC restriction in T cells?

T cell receptors only recognize antigens presented by self-MHC. Signup and view all the answers

What role do CD8 T cells play in virus infections?

CD8 T cells are the main controllers of viral infections. Signup and view all the answers

What factors influence the ability of a T cell receptor to bind to antigens?

The receptor must fit the ligand and recognize self-MHC. Signup and view all the answers

What is the initial response of the immune system when pathogens cross our barriers?

The innate immune response attempts to control the infection first. Signup and view all the answers

Which event leads to the activation of a CD4+ T cell?

Binding to an antigen presented by an APC along with costimulatory signals. Signup and view all the answers

What is the result of signals 1 and 2 during T cell activation?

Increased survival signals and robust proliferation occur. Signup and view all the answers

What does signal 3 dictate regarding the CD4+ T cell?

It dictates the type of CD4+ T cell it will differentiate into. Signup and view all the answers

What is the role of master regulators in T cell differentiation?

To control the expression of specific cytokines in response to activation. Signup and view all the answers

Which cytokines are associated with the development of Th1 cells?

IL-12 and interferon gamma Signup and view all the answers

Which of the following statements is true regarding TAP?

TAP is optimized to transport peptides of 9 amino acids with basic C terminal residues. Signup and view all the answers

How does Th1 and Th2 differentiation influence immune response?

Th2 cells suppress the development of Th1 cells. Signup and view all the answers

What role does Calnexin play in the MHC class I peptide loading process?

It acts as a chaperone protein to assist in the folding of the MHC alpha chain. Signup and view all the answers

What triggers cytokine production during T cell activation?

The interaction of PRRs with PAMPs. Signup and view all the answers

How does ERAP function in the processing of peptides for MHC class I?

It trims peptides to fit into the binding groove of MHC class I. Signup and view all the answers

Which T cell subset is associated with inflammatory diseases?

Th17 Signup and view all the answers

What is the function of tapasin in the peptide loading complex?

It transports MHC class I to TAP and positions it effectively for antigen binding. Signup and view all the answers

What is the fate of daughter cells created from activated T cells?

They can become either memory cells or effector cells. Signup and view all the answers

What happens to the MHC class I peptide complex after a tight binding antigen is formed?

It is released from tapasin and exits the peptide loading complex. Signup and view all the answers

What is the primary function of HLA-DM in the MHC class II pathway?

It catalyzes the release of CLIP from the peptide binding groove. Signup and view all the answers

What characteristic distinguishes the peptides presented by MHC class II from those presented by MHC class I?

MHC class II binds extracellular peptides that are approximately 22-24 amino acids long. Signup and view all the answers

How do CD8+ T cells interact with MHC class I molecules?

They recognize MHC class I/peptide complexes displayed on infected cells. Signup and view all the answers

What role does HLA-DO play in the MHC class II antigen processing pathway?

It blocks the function of HLA-DM, acting as a negative regulator. Signup and view all the answers

Which mechanism is utilized to present pathogen peptides on MHC class I during an infection?

Proteins are processed by the proteasome to form peptide fragments. Signup and view all the answers

Study Notes

Adaptive Immune Response

Adaptive immunity is found only in animals with jaws and backbones.
It enables a specific immune response against any pathogen (diverse).
It involves lymphocytes (B cells and T cells).
A primary response results in immune memory.
A secondary response (re-exposure to the same pathogen) is faster and stronger than the first.

Lymphocytes

Lymphocytes have two types of receptors: TCRs (T cell receptors) and BCRs (B cell receptors).
Both TCRs and BCRs are members of the immunoglobulin (Ig) superfamily.
TCRs and BCRs' functions are to recognize pathogens to initiate adaptive immune responses.
These receptors are randomly generated and highly diverse.
Self-reactive T cells are deleted in the thymus, and self-reactive B cells are deleted in the bone marrow.
Most TCRs have alpha and beta chains (TCRαβ).
Some TCRs have gamma and delta chains (TCRγδ).

Lymphocyte Receptors

TCRs do not bind to pathogens directly; they bind to short peptide fragments (primary structure) of a peptide receptor called MHC (major histocompatibility complex).
Class I MHCs are expressed on every cell in the body and present intracellular peptides to TCRs.
Class II MHCs are expressed on specialized antigen-presenting cells (APCs: macrophages, dendritic cells) and generally present extracellular peptides to TCRs.
BCRs bind to the three-dimensional (tertiary) structure of an antigen (e.g., part of a pathogen).
Antigens can be proteins, carbohydrates, lipids, or nucleic acids.

Lymphocyte Receptor Diversity

Lymphocyte receptors (TCRs and BCRs) are produced by random DNA rearrangement.
This process is called somatic recombination.

Somatic Recombination and Diversity

Many V(D)J and J combinations are possible.
Recombination of lymphocyte receptor DNA occurs early in lymphocyte development.
Mature lymphocytes express rearranged receptors on their surface.
This process results in lymphocyte diversity: lymphocytes generating a large, unique TCR and BCR repertoire.
T lymphocyte diversity occurs in the thymus.
B lymphocyte diversity occurs in the bone marrow.

Somatic Recombination

Multiple copies of gene segments (V, J, D, and C) coding for BCR and TCR proteins exist in the genome of immature lymphocytes.

RAG-1 and RAG-2

Recombination activating genes (RAG-1 and RAG-2) are enzymes expressed in immature B and T cells.
These enzymes randomly select and join V(D)J segments of a functional receptor gene.
Intervening DNA is removed.

TCR Rearrangement

TCR genes are made up of alpha and beta chains (most commonly) or gamma and delta chains.
TCR alpha and delta genes are found on chromosome 14 and contain multiple V, D, J exons.
TCR beta and gamma genes are found on chromosome 7 and contain multiple V and J exons (no D exons).
Rearranged TCRs express either αβ or γδ chains.

TCR Receptor Diversity

Immature T cells (thymocytes) travel to the thymus to undergo receptor rearrangement there.
The thymus undergoes a selection process but no further mutation.

Thymic Selection of Mature T Cells

Immature T cells (thymocytes) do not express a TCR initially.
Receptor rearrangement begins when thymocytes reach the subcapsular region of the thymus.
Rearrangement is random.
TCRs could be self-reactive and need to pass the selection process.

T Cell Selection

Positive selection: determines if the rearranged TCR is useful.
Lymphocytes expressing TCRs that can bind self MHC with low affinity receive a survival signal. TCRs that cannot bind to self MHC die.
Can the TCR recognize antigen in MHC?
Negative selection: determines if the rearranged TCR is dangerous.
Lymphocytes expressing TCRs that bind to self MHC with high affinity receive a signal to die (apoptosis).
The majority of thymocytes die (approximately 95%) during this process.
This establishes central tolerance (eliminating self-reactive T cells during T cell development).

What Happens to the Survivors?

The remaining 5% of lymphocytes express TCRs with intermediate affinity for self MHC.
This represents a highly diverse T cell repertoire (estimated to contain 10^16 - 10^18 unique TCRs).

Activation of Adaptive Immune System

B cells and T cells have receptors capable of binding antigen but not self.
They're ready to detect invading pathogens.

Main Cell Types of the Adaptive Immune Response

Helper T cells express CD4.
Cytotoxic (killer) T cells express CD8.
TRegs (regulatory T cells) suppress the activity of the above two populations.
Conventional B cells (B2 cells) rely on T cell help for activation.
Plasma cells are activated B cells that produce antibodies.
Unconventional B cells (B1 cells) are less diverse and less dependent on T cell help.
Lymphocytes that haven't seen an antigen before are called naïve lymphocytes;

Antigen Presentation

T cells are only activated in the presence of antigen-presenting cells (APCs).
APCs include dendritic cells (only APC for primary immune response), macrophages and B cells.
APCs present pieces of pathogens (8-24 amino acids) in their MHCs to the TCR.

Antigen Presentation (Reminder)

Dendritic cells exist in tissue in an immature state.
Their rate of entry into lymph nodes increases during inflammation.
Mature dendritic cells are in lymph nodes.

MHC Class I Presentation

Intracellular peptides (~9 amino acids long) are presented to CD8+ T cells.

Intracellular Peptides

Intracellular proteins are broken down into peptides in the cytoplasm by proteasomes.
There are two types of proteasomes: constitutive proteasome and immunoproteasome
The immunoproteasome is made by APCs and infected cells and preferentially degrades proteins into peptides that are compatible with MHC class I.
The peptides are then moved into the ER by TAP.

TAP

9 amino acid peptides are actively transported into the endoplasmic reticulum by the transporter associated with antigen processing (TAP).
TAP favors peptides with hydrophobic or basic C-terminal residues.
TAP pre-optimizes these peptides for transport into MHC class I.

MHC Class I Peptide Loading

Chaperone proteins like calnexin help fold MHC alpha chains.
The peptide loading complex, including tapasin, calreticulin and ERp57, bring MHC class I to TAP to ensure effective antigen binding.
ERAP (endoplasmic reticulum aminopeptidase) can trim peptides to better fit the MHC class I peptide-binding groove.
The complete MHC class I complex leaves the RER, goes through the Golgi (glycosylation), and moves to the plasma membrane.

MHC Class I Antigen Presentation

Almost all cells present self peptides in class I major histocompatibility complex (MHC).
If an infected cell presents pathogen peptides, these pathogens are eliminated by CD8+ T cells.

MHC Class II Binding Antigen

Class II MHC binds extracellular peptides (~22-24 amino acids long).
Newly synthesized class II alpha and beta chains bind to an invariant chain in the ER.
The invariant chain is a chaperone that prevents peptides from premature binding to the MHC complex while it is in the ER that stops peptides from binding to the peptide-binding groove.
Extracellular pathogens/antigens are taken into the cell by phagocytosis or endocytosis.
The phagosome/endosome acidifies, fuses with lysosomes, and the pathogen is degraded into peptides, which bind and replace the invariant chain/CLIP in the class II peptide-binding groove of the MHC complex.

MHC Class II Peptide Complex Transport

The class II MHC peptide complex is transported to the plasma membrane
Different MHC molecules will have different spectra of peptides, based on varying anchor residues.

Naïve CD8+ T Cell Activation

Naïve CD4+ T cells are activated when they recognize extracellular pathogen-derived peptides.
Naïve CD8+ T cells usually need cross-presentation by APCs.

Cross-Presentation

APCs activate naïve CD4+ T cells initially.
The activated CD4+ T cells then send messages to the APC, and now this APC can also cross-present antigens recognized by CD8+ T cells.

Activated T Cells

Activated killer T cells circulate throughout the body and enter inflamed tissue to recognize and eliminate virus infected cells.
Activated helper T cells move to where they are needed to help modulate the immune response.

Memory T Cells

After activation of T cells there is rapid clonal expansion.
The pathogen is cleared, and 90-95% of T cells die by apoptosis.
Leftover T cells are antigen-specific memory T cells.
These memory cells react faster, with a stronger response to a re-infection with the same pathogen, than a naïve T cell.

Cytotoxic T Lymphocytes (CTLs)

CTLs are the third wave of antiviral response.
CTLs represent the only way to eliminate infected cells through the killing of virus infected cells.

CTL Activation

Process: (1) Activation (2) Recognition (3) Killing

CTL Recognition and Killing

CTLs bind to antigen-presenting cells (APCs) expressing specific antigens.
CTLs recognize viral antigens and kill infected cells.

CTL Cell Death Mechanisms

Granule exocytosis: CTLs release granzymes into the target cell through perforin pores that induces apoptosis
Receptor-mediated apoptosis: CTLs stimulate the death receptors (Fas/FasL) on target cells to induce apoptosis.

Overview of Adaptive Immune Response Activation

A comprehensive diagram summarizing antigen entry, activation of antigen-presenting cells (APCs) (e.g., dendritic cells), and T cell activation.
This diagram visually shows how the various cell types and molecules work together during the adaptive immune response.

T Cell Activation

The activation of helper T cells (TH) is the first step to induce adaptive immune responses.
The activation process generally occurs in secondary lymphoid organs such as lymph nodes, spleen, or Peyer's patches.

T Cell Activation: Signal 1, 2, and 3

Signal 1: TCR binding to MHC/peptide complex
Signal 2: Co-stimulatory molecules (e.g., CD28/CD80/86) binding
Signal 3: Cytokines produced by the APC

APC Co-stimulatory Molecule Expression

Co-stimulatory molecules (e.g. CD80/86) are upregulated by APCs in response to pathogen-associated molecular patterns (PAMPs) detected by Pattern Recognition Receptors (PRRs).
Only after these signals and binding to the APC and receptors, the T cell is fully activated and can produce effector cytokines
Co-stimulatory molecules are important to initiate and control T cell responses

TCR Signaling

Specific binding of a TCR to an appropriate MHC/peptide complex
Co-receptor (CD4 or CD8) binding to MHC class II or class I, respectively.

Studying That Suits You

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Description

This quiz explores key concepts related to adaptive immune receptors and T cell receptors. It covers their functions, the cells responsible for adaptive immunity, and the processes involved in T cell development and selection. Test your knowledge on receptor rearrangement and the diversity of the T cell receptor repertoire.