Immunology I: T-Cell Receptor Structure and Content Recognition and Adaptive Immune Response

Course Information and Learning Objectives

• Course Title: Immunology I (34210A)

• Instructor: Dr. Abdulmajeed Almutary

• Date: June 8, 2026

• Institution: Abu Dhabi University, Spring Semester 2025-2026

• Session Focus: Recognition of antigen by B and T cell receptors in the context of the Adaptive immune response.

• Key Learning Outcomes:

  • Comprehensive understanding of the structure and function of T cell receptors (TCR).

  • Knowledge of Natural Killer (NK) cells and dendritic cells.

  • Mechanisms of action in cell-mediated responses against infected cells.

Overview of T Lymphocytes

• Major Populations: Adaptive immunity involves two primary lymphocyte populations:

  • B lymphocytes (B cells)

  • T lymphocytes (T cells)

• Origin: T cells originate from hematopoietic stem cells located in the bone marrow.

• Maturation:

  • Immature T cells migrate from the bone marrow to the thymus gland for maturation.

  • In the thymus, T cells mature and begin expressing specific surface receptors.

• Differentiation: Daughter T cells differentiate into two functional categories:

  1. Memory T cells

  2. Effector T cells

• Type of Immunity: The immune response mediated specifically by T cells is known as cell-mediated immunity (or T-cell mediated immunity).

T Cell Receptors and Surface Markers

• T cells express a variety of receptors on their surface, classified as Clusters of Differentiation (CD):

  • CD3 (Cluster of Differentiation 3): A core receptor expressed by T cells.

  • CD4 (Cluster of Differentiation 4): Expressed by Helper T lymphocytes.

  • CD8 (Cluster of Differentiation 8): Expressed by Cytotoxic T lymphocytes (CTL).

  • CD28 (Cluster of Differentiation 28): Acts as the receptor for interactions with antigen-presenting cells (APCs).

  • CD45 (Cluster of Differentiation 45): Involved in the signaling pathways of immune cells.

Hematopoiesis and Lineage

• Stem Cells: Self-renewing hematopoietic stem cells give rise to two main lineages:

  • Myeloid Progenitor: Leads to the formation of Dendritic cells, Macrophages, Monocytes, Granulocyte-monocyte progenitors (Neutrophils, Eosinophils, Basophils), Megakaryocytes (Platelets), and Erythroid progenitors (Erythrocytes).

  • Lymphoid Progenitor: Leads to the formation of Natural Killer (NK) cells, T-cell progenitors (Differentiating into $T_H$ helper cells and $T_C$ cytotoxic T cells), and B-cell progenitors (Differentiating into B cells).

• Dendritic Cell Origin: Note that dendritic cells can originate from either lymphoid progenitors or myeloid precursors.

Antigen Recognition and Presentation

• Recognition Constraints: T cells cannot recognize soluble antigens in their free form.

• The Presentation Process:

  1. An antigen must be presented to the T cell receptor by an Antigen-Presenting Cell (APC).

  2. This presentation occurs via Major Histocompatibility Complex (MHC) molecules.

• Antigen-Presenting Cells (APCs): These include macrophages, B cells, dendritic cells, neutrophils, basophils, eosinophils, and platelets.

• Function of APCs:

  • They express MHC molecules on their surface.

  • They cleave or process antigens into smaller fragments.

  • Post-processing, the specific epitopes of the antigen are expressed on the MHC molecules.

  • T cells recognize these epitopes, bind to the MHC-antigen complex, and initiate the immune response.

Major Histocompatibility Complex (MHC) Classes

• MHC molecules are permanent fixtures on APCs. There are two primary classes based on binding affinity:

MHC Class I

• Function: Enables the body to recognize and destroy infected cells with the help of Cytotoxic CD8 T cells.

• Distribution: Present on lymphocytes, neutrophils, basophils, eosinophils, and platelets.

• Structural Binding:

  • Possesses a deep groove for binding antigen epitopes.

  • Typically binds peptides that are $8-11$ amino acid residues long.

  • Contains "anchor residues" within allele-specific pockets to secure the peptide in the groove.

• Mechanism: When an APC processes a virus (antigen), MHC-I displays a peptide epitope on the cell surface. CD8 T cells bind to this MHC:antigen peptide complex to facilitate killing the target.

MHC Class II

• Function: Enables CD4 T cells to recognize epitopes and trigger the release of cytokines and other immune cells to kill the antigen.

• Distribution: Present exclusively on professional APCs such as dendritic cells, macrophages, and B-lymphocytes.

• Structural Binding:

  • The peptide-binding cleft is open at both ends, allowing longer peptides to extend beyond the groove.

  • Accommodates peptides of $10-30$ amino acids (specifically specified as $13-18$ or $12-17$ amino acid residues in different structural models).

  • Bound peptides maintain a roughly constant elevation on the floor of the binding cleft.

• Phagocytic Mechanism:

  1. Pathogens (bacteria, fungi, protozoa, free viruses) are engulfed via phagocytosis into a phagosome.

  2. Lysosomes fuse with the phagosome to digest the pathogen into short peptides.

  3. Immunodominant epitopes associate with MHC-II and are presented on the surface for CD4 T cell recognition.

Structure of T Cell Receptors (TCR)

• Chain Composition: The TCR is a heterodimer composed of two transmembrane glycoprotein chains: the $\alpha$ (alpha) chain and the $\beta$ (beta) chain.

• Domain Structure:

  • Amino Terminus ($NH_2$): Contains the Variable (V) regions ($V_{\alpha}$ and $V_{\beta}$). These regions are highly variable and contain Hypervariable or Complementarity Determining Regions (CDR) which act as the antigen-binding sites.

  • Carboxyl Terminus ($COOH$): Contains the Constant (C) regions ($C_{\alpha}$ and $C_{\beta}$). These determine the functional properties of the T cell.

• Structural Components:

  • Carbohydrate Side Chains: Attached to each domain.

  • Disulfide Bond: Connects the $\alpha$ and $\beta$ chains between their constant regions.

  • Stalk Segment: Connects the external domains to the transmembrane region.

  • Transmembrane Region (Tm): Anchors the receptor in the lipid bilayer.

  • Cytoplasmic Tail (CT): Short segments at the carboxyl-terminus (lengths of approximately $248$ and $282$ residues are noted in diagrams).

Functional Comparison of CD4 and CD8 T Cells

• Commonalities: Both are involved in antigen binding and signal transmission to stimulate immune responses.

• Key Differences:

  • CD8 T Cells (Cytotoxic T Cells):

    • Recognize antigens bound to MHC Class I.

    • Act as cytotoxic cells capable of killing antigens through direct interaction.

    • Defend against intracellular pathogens (viruses, bacteria, cancer).

  • CD4 T Cells (Helper T Cells):

    • Recognize antigens bound to MHC Class II.

    • Role is primarily activation and initiation of other immune components.

Specific Mechanisms of CD8 T Cells

Once activated by an MHC-I:antigen complex, CD8 T cells utilize three major killing mechanisms:

1. Cytokine Secretion: Release of pro-inflammatory and cytotoxic cytokines, specifically Tumor Necrosis Factor-alpha (TNF-$\alpha$) and Interferon-gamma (IFN-$\gamma$), to facilitate effective killing.

2. Cytotoxic Granule Release:

   • Perforin: Forms cylindrical structures that insert into the lipid bilayer of the target cell membrane, creating pores.

   • Granzymes: Enter through these pores. The loss of membrane integrity allows water and salts to enter the cell rapidly, leading to cell death through DNA fragmentation.

3. Fas-Mediated Apoptosis:

   • Interaction between FasL (on T cell) and Fas (on target cell) programs the target for apoptosis.

   • Apoptosis Characteristics: Includes nuclear blebbing, changes in cell morphology, and DNA fragmentation. Simple terms: the cell shrinks, sheds vesicles, and degrades itself from within.

Specific Mechanisms of CD4 T Cells

Once activated, CD4 T cells initiate the following:

1. Immune Cell Activation: Activates cells of the innate immune system, B-lymphocytes (for antibody production), and Cytotoxic T cells.

2. Non-Immune Cell Activation: Activates epithelial cells, epidermal keratinocytes, mesenchymal cells, stromal cells, and fibroblasts. These cells then release bioactive molecules (lymphotoxins, neurotransmitters) that modulate the production of immune-suppressive cytokines to control the reaction.

Pathological Conditions Related to T Cells

Severe Combined Immunodeficiency (SCID)

• Definition: An immunodeficiency disease characterized by the combined absence of both T lymphocyte and B lymphocyte function.

• Prognosis: Fatal without a stem cell transplant or corrective gene therapy.

• Colloquial Name: Known as "bubble baby disease" because patients must live in sterile environments due to extreme vulnerability to infections.

Hemophagocytic Lymphohistiocytosis (HLH)

• Definition: A disorder involving excessive T cell activation and inflammatory cytokine production.

• Pathology: Macrophages become overactive and engulf blood cells (erythrocytes, leukocytes, or platelets). Lymphocytes collect in the spleen and liver, causing organ enlargement and progressive multiorgan failure.

• Types of HLH:

  1. Familial HLH: Accounts for $25\%$ of cases. Inherited genetically. If both parents are carriers: $25\%$ chance the child is affected, $25\%$ chance the child is healthy, and $50\%$ chance the child is a carrier.

  2. Acquired HLH: Caused by external conditions including viral infections (notably Epstein-Barr virus/EBV), other infections, cancer, or a diseased immune system.