Cell-Mediated Adaptive Immunity: T Cell Activation, Differentiation, and Effector Functions

Cell-Mediated Adaptive Immunity

Overview of T Cell-Mediated Immunity

The cell-mediated branch of adaptive immunity is primarily driven by T lymphocytes (T cells), which are responsible for recognizing and responding to specific antigens presented by antigen-presenting cells (APCs). This process is essential for defending the body against intracellular pathogens, such as viruses and some bacteria, as well as for regulating immune responses.

T Cell Activation and Differentiation

Priming of Naïve T Cells

• Naïve T cells circulate in the blood and lymphatic system, constantly surveilling for antigens.

• They encounter antigen-presenting cells (APCs) in secondary lymphoid tissues (e.g., lymph nodes, spleen) that display peptide antigens bound to major histocompatibility complex (MHC) molecules.

• Main types of APCs: dendritic cells, macrophages, and B cells.

Antigen Presentation by APCs

• APCs engulf pathogens at infection sites and migrate to secondary lymphoid tissues to present antigens to T cells.

• Dendritic cells are the most potent APCs for activating naïve T cells.

• Macrophages and B cells also present antigens but have specialized roles (see below).

Role of Dendritic Cells in Antigen Presentation and T-Cell Activation

• Antigen uptake and presentation: Dendritic cells phagocytose pathogens, process antigens, and present them on MHC molecules.

• Maturation: Immature dendritic cells in peripheral tissues capture antigens and migrate to lymphoid tissues, where they mature and upregulate costimulatory molecules (e.g., B7).

• Mature dendritic cells have numerous cellular projections (dendrites) that facilitate interaction with naïve T cells.

• They secrete chemokines (e.g., CCL18) to attract T cells for efficient antigen presentation.

Role of Macrophages in Antigen Presentation and T-Cell Activation

• Macrophages are primarily specialized for phagocytosis and destruction of pathogens.

• They can present antigens to T cells, especially in the context of ongoing infection and inflammation.

• Macrophages are important for activating effector T cells at sites of infection.

Role of B Cells in Antigen Presentation and T-Cell Activation

• B cells internalize antigens via their immunoglobulin (Ig) receptors and present processed peptides on MHC class II molecules.

• Antigen presentation by B cells is highly specific to the antigen recognized by their Ig receptor.

• B cells play a major role in activating helper T cells during humoral immune responses.

T Cell Migration and Homing

Migration into Secondary Lymphoid Tissue

• T cells exit the bloodstream and enter secondary lymphoid tissues through specialized blood vessels called high endothelial venules (HEVs).

• This process is guided by chemokines (e.g., CCL21) and adhesion molecules (e.g., L-selectin, LFA-1).

• Naïve T cells express the chemokine receptor CCR7, which binds to CCL21, facilitating their entry into lymphoid tissues.

• If not activated, T cells exit via efferent lymphatics, a process regulated by sphingosine-1-phosphate.

Mechanisms of T Cell Activation

Signals Required for T Cell Activation

• Signal 1: T cell receptor (TCR) recognition of antigenic peptide presented by MHC on APCs.

• Signal 2 (Costimulation): Interaction between CD28 on T cells and B7 molecules (CD80/CD86) on APCs.

• Costimulation is essential to prevent T cell anergy (non-responsiveness) and ensure proper activation.

• APCs upregulate B7 in response to pathogen recognition via pattern recognition receptors (e.g., TLRs).

Immunological Synapse Formation

• The interface between a T cell and an APC forms an immunological synapse, organizing receptors, coreceptors (CD4/CD8), and adhesion molecules for efficient signaling.

Signal Transduction Pathways in T Cell Activation

• TCR and CD3 complex initiate intracellular signaling upon antigen recognition.

• CD3 proteins contain ITAMs (immunoreceptor tyrosine-based activation motifs) that are phosphorylated by the tyrosine kinase Lck.

• ZAP-70 is recruited and activated, leading to downstream signaling cascades.

• Three major pathways are activated:

  • Calcium-NFAT pathway: IP3 increases intracellular Ca2+, activating calcineurin, which dephosphorylates NFAT, allowing it to enter the nucleus and promote gene transcription.

  • PKC-NFκB pathway: DAG activates PKC-θ, which activates NFκB, a transcription factor for T cell activation genes.

  • Ras-MAPK pathway: Ras activates MAPK, leading to activation of transcription factors such as Fos and Jun (AP-1 complex).

Role of Interleukin-2 (IL-2) in T Cell Activation

• IL-2 is a key cytokine produced by activated T cells.

• It promotes T cell proliferation and clonal expansion.

• Activated T cells upregulate the high-affinity IL-2 receptor, allowing them to respond to IL-2 and proliferate.

T Cell Differentiation and Effector Functions

Types of Effector T Cells

• Cytotoxic T cells (CD8+): Destroy infected or abnormal cells.

• Helper T cells (CD4+): Coordinate immune responses by activating other immune cells.

• Regulatory T cells (Treg): Suppress immune responses to maintain tolerance and prevent autoimmunity.

• Natural Killer T (NKT) cells: Share features of both T cells and NK cells, recognizing lipid antigens presented by CD1d molecules.

Effector T Cell Functions and Cytokine Utilization

• Effector T cells secrete cytokines to modulate immune responses.

• Cytokine signaling involves JAK-STAT pathways, leading to gene expression changes in target cells.

• Different T cell subsets produce distinct cytokines to direct specific immune responses.

Mechanisms of Cytotoxic T Cell-Mediated Killing

• Cytotoxic T cells induce apoptosis in target cells to prevent pathogen spread and tissue damage.

• Mechanisms include:

  • Release of cytotoxic granules containing perforin (forms pores) and granzymes (activate apoptosis).

  • Expression of Fas ligand (FasL), which binds to Fas on target cells, triggering apoptotic pathways.

Functions of Helper T Cell Subsets

• Th1 cells: Activate macrophages via IFN-γ and CD40L, enhancing intracellular pathogen killing.

• Th2 cells: Activate B cells for antibody production (especially IgE) and stimulate granulocytes (e.g., eosinophils) for defense against parasites.

• Tfh (follicular helper) cells: Promote B cell activation, proliferation, and differentiation in germinal centers.

• Th17 cells: Induced by TGF-β and IL-6, secrete IL-17 to recruit neutrophils and clear extracellular bacteria and fungi.

Functions of Regulatory T Cells (Treg)

• Suppress activation of helper and cytotoxic T cells to maintain immune homeostasis.

• Express the transcription factor Foxp3 and secrete anti-inflammatory cytokines (e.g., IL-10, TGF-β).

• Prevent autoimmunity by controlling self-reactive T cells.

Functions of Natural Killer T (NKT) Cells

• Develop in the thymus and express a semi-invariant TCR that recognizes glycolipid antigens presented by CD1d molecules.

• Bridge innate and adaptive immunity by responding rapidly to certain bacterial infections.

Summary Table: Major Antigen-Presenting Cells and Their Functions

APC Type	Main Function	Antigen Uptake Mechanism	Role in T Cell Activation
Dendritic Cell	Initiates T cell responses	Phagocytosis, macropinocytosis	Activates naïve T cells
Macrophage	Phagocytosis, pathogen destruction	Phagocytosis	Activates effector T cells at infection sites
B Cell	Antibody production	Receptor-mediated endocytosis	Presents antigen to helper T cells

Key Terms and Definitions

• Antigen-presenting cell (APC): A cell that processes and presents antigens to T cells via MHC molecules.

• Major histocompatibility complex (MHC): Cell surface proteins essential for antigen presentation to T cells.

• Costimulation: Additional signal required for full T cell activation, typically via CD28-B7 interaction.

• Cytokine: Small protein released by cells that affects the behavior of other cells, crucial in immune signaling.

• Immunological synapse: Structured interface between a T cell and an APC for effective communication and signaling.

Relevant Equations and Pathways

• Calcium-NFAT Pathway:

$IP_3 \rightarrow \text{Ca}^{2+} \uparrow \rightarrow \text{Calcineurin activation} \rightarrow \text{NFAT dephosphorylation} \rightarrow \text{NFAT nuclear translocation}$

• PKC-NFκB Pathway:

$DAG \rightarrow \text{PKC-}\theta \rightarrow \text{NF}\kappa\text{B activation} \rightarrow \text{Gene transcription}$

• Ras-MAPK Pathway:

$\text{Ras} \rightarrow \text{MAPK cascade} \rightarrow \text{Fos/Jun (AP-1) activation} \rightarrow \text{Gene transcription}$

Summary

• T cell-mediated immunity is essential for adaptive immune responses against intracellular pathogens and for immune regulation.

• Activation requires antigen presentation, costimulation, and complex intracellular signaling.

• Effector T cells differentiate into specialized subsets with distinct roles in immunity and tolerance.