T cell activation, receptors, and development

• T cell activation, receptors and development have implications for autoimmunity

T Cell Receptor Details

• T cell receptors (TCRs) scan molecules to check for self or non-self antigens
• TCRs are handheld scanners made of two parts
• Alpha chain is one side of scanner
• Beta chain is other side
• Each chain has two sections
• Variable region
• Constant region
• The tip of the scanner binds to an antigen and functions as the scanning sensor
• The base of the scanner keeps it stable

How T Cell Receptor Scanners Work

• A pathogen piece, or antigen, is shown to T cells by an MHC protein
• The TCR binds to the antigen-MHC complex to see if it's dangerous
• The immune response attacks if TCR recognizes antigen as foreign

Antigen Presentation to T Cells

• Macrophages (APCs) swallow pathogens, breaking them into small pieces (antigens)
• T cells cannot directly see an infection, so macrophages present the antigen on the surface using MHC
• MHC 1 presents antigens from inside viruses
• MHC 11 presents antigens from outside bacteria
• TCRs on T cells scan the MHC-antigen complex to see if the antigen is a threat
• Once activated, T cells signal other immune cells, like B cells and killer T cells, to attack, making antibodies

Effector Functions of Cytotoxic T Lymphocytes

• Killer T cells find the affected tumor or virally infected cell

Ways killer T cells destroy enemy cells

• Killer T cells release perforin which pokes holes in the target cell
• Granzyme B enters through the holes, causing apoptosis
• Killer T cells use the Fas ligand (FasL), or death hand shake
• FasL binds to Fas antigen on the target cell, which triggers apoptosis
• Killer T cells and NK cells use TRAIL, which binds to death receptors on target cells, causing self-destruction

T Cell and APC Interaction

• APCs like dendritic cells and macrophages show pieces of a pathogen to T cells
• T cells (CD4+ T cells) communicate with APCs using protein interactions to determine if a reaction is needed

Key interactions

• MHC on APC presents foreign antigen to TCR (T cell receptor) on T cell
• CD4 (on T cell) stabilizes connection between MHC and TCR to make sure the message is received
• CD80 on APC binds to CD28 (on T cell)
• This sends a co-stimulatory signal to activate the T cell
• Adhesion molecules (LFA-1, ICAM-1, VLA-4) strengthen contact between APC and T cell

B-Cell Receptors

• Found on B cells
• Are membrane-bound antibodies (IgM and IgD) that recognize specific pathogens
• Unlike TCRs, BCRs can be secreted into the blood as antibodies to help fight infections

Comparison to T Cell Receptors

• BCRs can bind directly to floating antigens, unlike TCRs
• BCRs contain two chains, which is different from TCRs
• They contain V and C regions like TCRs

T Cell Receptor Complex & CD3 Co-Receptor Role

• TCRs, alone, cannot send a signal
• TCRs must activate helper proteins to initiate cell signaling
• TCR (alpha and beta chains) recognizes antigens presented by MHC molecules
• CD3 complex helps with signaling
• CD3 proteins (γ, δ, ε, and ζ chains) send signals into the cell
• These proteins help the T cell express the TCR on the cell surface
• Transmit an activation signal once the antigen is recognized
• When TCR binds to an antigen presented by an APC, the CD3 complex sends signals inside of the T cell

CD4 and CD8 Co-Receptors

• CD4 and CD8 are co-receptors found on different T cells, help recognize and interact with infected cells, and function like adhesion molecules
• They are also co-signaling receptors that enhance activation signals
• CD4 is found on helper T cells
• Binds to MHC II molecules on APCs
• Activates immune cells like B cells and macrophages
• CD8 is found on cytotoxic T cells
• Binds to MHC I molecules found on nucleated cells
• Kills infected or cancerous cells
• CD4 binds to the β2 domain of MHC II while CD8 binds to the α3 domain of MHC I

CD4 T Cell Activation

• Signal 1 involves antigen recognition
• TCR binds to MHC II molecules on the APC
• Only happens if MHC II is presenting a specific antigen
• CD4 further strengthens the bond by attaching to MHC II
• Signal 2 involves co-stimulation
• A CD28 receptor on the T cell binds to the B7 molecule on the APC
• Creates a double-check system to make sure T cells are only activated when needed
• With only signal one, T cells are not fully activated

CD8 T Cell Activation

• (TCR) binds to MHC Class 1 Molecule of APC
• CD8 strengenthns the binding by attaching to α3 domain of MHC I

T Cell Selection

• T cells need to recognize MHC molecules during cortex positive selection
• T cells survive if they bind
• If a T cell fails to recognize MHC, it dies
• Goal is to keep T cells that can recognize MHC molecules; these cells become mature CD4+ or CD8+ T cells
• T cells that could attack the body's own cells are removed during medulla negative selection
• T cell differentiation explains how naive CD4+ T cells differentiate into different effector T helper (TH) subsets

T Helper (TH) Subsets

• Activation of a naive CD4+ T cell is Step 1
• The naive CD4+ T cell then becomes an immature helper T cell
• Different polarizing cytokines, or chemical signals, influence the naive T cells to develop into a type of T helper (TH) cell during Step 2

Key Characteristics of T Cell Subsets

• TREG (regulatory T cells):
• Influenced by IL-2 and TGF-β
• Suppresses immune responses and prevents excessive inflammation
• Helps prevent autoimmunity and may also inhibit antitumor responses
• TH17 (helper 17 cells):
• Influenced by IL-6, IL-23, and TGF-β
• Fights bacteria and fungi in barrier tissues such as the gut and skin
• Is involved in autoimmune diseases and tissue inflammation
• TH2 (helper 2 cells):
• Influenced by IL-4
• Helps fight helminths (parasitic worms) and activates eosinophils
• Linked to allergies (overreaction of the immune system)
• TH9 (helper 9 cells):
• Influenced by IL-4 + TGF-β
• Fights extracellular parasites, including worms
• Plays a role in autoimmunity
• TFH (follicular helper T cells):
• Influenced by IL-6 and IL-21
• Helps B cells produce antibodies and supports germinal center formation
• Helps in antibody responses but can also lead to autoimmunity
• TH1 (helper 1 cells):
• Influenced by IL-12, IFN-γ, and IL-18
• Fights intracellular pathogens (viruses and bacteria) and activates macrophages
• Can cause tissue inflammation
• TH22 (helper 22 cells):
• Influenced by IL-6 and TNF-α
• Protects skin from infection by fighting extracellular bacteria
• Can contribute to inflammatory skin diseases