Adaptive Immunity and T Cell Receptors

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.

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.