Immunology I - T Lymphocytes and Antigen Recognition

T Lymphocytes

Major Lymphocytes of the Adaptive Immune Response

• The two major populations of lymphocytes involved in adaptive immunity:

  • B lymphocytes (B cells)

  • T lymphocytes (T cells)

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

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

• In the thymus, T cells mature and express various receptors.

• Daughter T cells differentiate into memory T cells and effector T cells.

• Immune response mediated by T cells is known as cell-mediated immunity (or T-cell mediated immunity).

T Cell Receptors

T cells express different receptors on their surface:

• CD3 (Cluster of Differentiation 3)

• CD4 (Cluster of Differentiation 4): Commonly known as Helper T lymphocytes

• CD8 (Cluster of Differentiation 8): Commonly known as Cytotoxic T lymphocytes (CTL)

• CD28 (Cluster of Differentiation 28): Receptor for antigen-presenting cells

• CD45 (Cluster of Differentiation 45): Receptor for signaling of immune cells

T Cells and Antigen Recognition

• T cells do not recognize soluble antigens in free form.

• Antigens must be presented to the T cell receptor by antigen-presenting cells (APCs) with the help of Major Histocompatibility Complex (MHC) molecules.

Antigen Presenting Cells

• Antigen-presenting cells (APCs) include macrophages, B cells, dendritic cells, neutrophils, basophils, eosinophils, and platelets.

• These cells express Major Histocompatibility Complexes (MHC) molecules on their surface.

• The role of APCs is to cleave or process antigens into smaller fragments (epitopes).

• Epitopes of an antigen are then expressed on the MHC molecules.

• T cells can only recognize antigens when presented by the MHC molecules of APCs.

• After recognizing and binding to the antigen, T cells can initiate an immune response.

Major Histocompatibility Complex (MHC)

• MHC molecules are present on antigen-presenting cells.

• Two classes of MHC molecules:

  • MHC-class I: Specifically bind to CD8 T cell receptors (cytotoxic T cells)

  • MHC-class II: Specifically bind to CD4 T cell receptors (helper T cells)

• MHC class I and MHC class II differ in structure and expression pattern.

MHC-class I

• Designed to enable the body to recognize infected cells and destroy them with CD8 T cells.

• Present on lymphocytes (B cells), neutrophils, basophils, eosinophils, and platelets.

• Possess a deep groove that can bind antigen epitopes of 8-9 amino acids long.

• When an APC processes an antigen (e.g., a virus), MHC-class I displays a part of this antigen (epitope) on the lymphocyte cell surface.

• CD8 T cells then bind to the MHC-class I molecule, forming a complex that helps kill the antigen.

• Peptide-binding cleft in MHC class I molecules is blocked at both ends, accommodating small antigens (8–9 amino acid residues).

• Amino acid residues on the antigen are called anchor residues, allowing the antigen to attach tightly to the groove of the MHC molecule.

• Any antigen peptide of the correct length with anchor residues that fit the MHC groove will bind to the MHC class I molecule.

MHC-class II

• Designed to enable CD4 T cells to recognize antigen peptides (epitopes) and initiate the release of cytokines and immune cells to kill the antigen.

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

• Possess a deep groove that can bind peptide epitopes of 12-17 amino acids long.

• The peptide-binding cleft in class II molecules is open, allowing longer antigen peptides (12-17 amino acids) to fit into the groove.

• Peptides that bind to MHC class II molecules contain an internal sequence (anchor residues) that serve as major contact points between the antigen and the MHC Class II molecule.

• Antigens such as bacteria, fungi, protozoa, and free viruses are first phagocytosed into short peptides by APCs.

• APCs express fragments of this antigen peptide on MHC-class II molecules.

• CD4 T cells bind to these MHC-class II molecules and form a complex that initiates an immune response against the antigen.

Structure of T Cell Receptors (CD4 and CD8)

• Composed of two transmembrane glycoprotein chains:

  • α chain

  • β chain

• Each chain has an amino terminus and a carboxyl terminus.

• The amino terminus of the two chains consists of a Variable (V) region, while the carboxyl terminus consists of the Constant (C) region.

• The variable region (V) is highly variable and comprises hypervariable or complementarity-determining regions (CDR), which serve as the antigen-binding site.

• The constant regions are not variable and determine the functionality of the T cells.

• Both chains have carbohydrate side chains attached to each domain.

• The α and β chains are connected by a disulfide bond between their constant regions.

• Each α and β chain contains a short cytoplasmic tail at the carboxyl-terminal end.

• A short stalk segment connects the domains to the transmembrane region.

T-Cell Receptors: CD4 and CD8 receptors

• T cells can be subdivided into two populations according to their expression of CD4 or CD8 membrane receptors.

• Both CD4 and CD8 are involved in antigen binding and signal transmission for stimulating an immune response against the antigen.

• The main difference between the two receptors is that:

  • CD8 T cell receptors recognize antigens bound to MHC-class I molecules of the antigen-presenting cell.

  • CD8 T cells, called cytotoxic cells, can kill the antigen by direct interaction.

  • CD4 T cell receptors recognize antigens bound to MHC-class II molecules of the antigen-presenting cell.

  • CD4 T cell receptors initiate the release of cytokines and immune cells to kill the antigen.

Functions of CD8 T cells

• CD8 T cells, called cytotoxic T cells, are important for immune defense against intracellular pathogens, including viruses, bacteria, and cancer cells.

• When a CD8 T cell recognizes its antigen and becomes activated, it has three major mechanisms to kill infected cells:

  1. Secretion of cytokines, mainly Tumor Necrosis Factor-alpha (TNF-α) and Interferon-gamma (IFN-γ).

  2. Production and release of cytotoxic granules, perforin and granzymes.

  3. Apoptotic cell death (programmed cell death) through Fas molecules.

Mechanism 1: Secretion of Cytokines

• Large numbers of pro-inflammatory cytokines are released by CD8 T cells.

• Pro-inflammatory cytokines generally regulate growth, cell activation, differentiation, and homing of immune cells to the sites of infection, with the aim to control and eradicate intracellular pathogens, including viruses.

Mechanism 2: Production and Release of Cytotoxic Granules

• Granules from cytotoxic CD8 T cells include Granzymes and Perforins.

• These granules are cytotoxic and can lyse (kill) antigens by creating pores in the lipid bilayer of the antigen.

• Perforins are released, forming a cylindrical structure that inserts into the lipid bilayer of the antigen cell membrane, creating a pore that allows water and ions to pass rapidly out of theantigen.

• Granzymes enter the antigen, after the pores are made, and degrade the antigen cellular DNA by fragmentation.

• The outer layer of the cell membrane is destroyed by perforins, and the inner proteins/DNA within the antigen are destroyed by granzymes, causing antigens to die rapidly by fragmentation of cellular DNA and cell lysis.

Mechanism 3: Apoptotic Cell Death Through Fas Molecules

• Cytotoxic CD8 T cells kill the antigen by programming them to undergo apoptosis (programmed cell death).

• Apoptosis is a cellular response resulting in cellular changes such as:

  • nuclear blebbing

  • alteration in cell morphology

  • fragmentation of the DNA.

• The cell destroys itself from within, shrinking by shedding membrane-bound vesicles and degrading itself until little is left.

Functions of CD4 T cells

• CD4 T cells, called Helper T cells, have dual functions:

  • Activating immune cells for antigen killing.

  • Suppressing the immune response once the antigen has been eliminated from the host.

• A CD4 T cell recognizes the antigen and becomes activated to either:

  • Activate the cells of the innate immune system, B-lymphocytes, and cytotoxic CD8 T cells by releasing pro-inflammatory cytokines.

  • Activate non-immune cells (e.g., epithelial cells, mesenchymal cells, stromal cells) by releasing bioactive molecules such as lymphotoxins and neurotransmitters that modulate immune cells to produce immune-suppressive cytokines (anti-inflammatory cytokines).

Mechanism 1: Activation of the Cells of the Innate Immune System, B-Lymphocytes and Cytotoxic CD8 T Cells

• Large numbers of pro-inflammatory cytokines are released by the CD4 T cells to help combat the infection.

• CD4 helper T cells determine which cytokines will allow the immune system to be most useful or beneficial for the host.

• The cytokines released by CD4 also help the CD8 T cells to become active against the antigen.

Mechanism 2: Activation of Regulatory Immune Cells

• A large number of anti-inflammatory cytokines are released by the CD4 T cells once the antigen has been eliminated to regulate the immune response.

• The anti-inflammatory cytokines activate immune-suppressive cells known as regulatory T cells (Tregs), that allow suppression of the immune cells.

• Downregulates CD4 and CD8 T cells and other activated immune cells once the antigen has been eliminated from the host.

Diseases Related to T Cell Deficiency

Severe Combined Immunodeficiency (SCID)

• Immunodeficiency disease in which there is a combined absence of T lymphocyte and B lymphocyte function.

• SCID is fatal without a stem cell transplant or corrective gene therapy.

• Also known as the "bubble baby" disease because its victims are extremely vulnerable to infectious diseases and some are kept in a sterile environment for life.