T-Cell Activation

Introduction

• The activation of T-cells must be tightly controlled to allow for
  • selective proliferation of pathogen specific T-cells
  • anergy of self-reactive T-cells
  • prevention of autoimmune disorders
• Four events are required for proper T-cell activation including
  • antigen processing and presentation by antigen presenting cells that 
    • display antigens as peptides bound to MHC
    • migrate to draining lymph nodes
  • specific binding of the T-cell receptor to the antigen concurrently with
    • binding of CD4 coreceptors to MHC class II in helper T-cells
    • binding of CD8 coreceptors to MHC class I in killer T-cells
  • costimulation of the T-cell by antigen presenting cells through interaction between
    • B7 (CD80/CD86) on dendritic cells
    • CD28 on T-cells
  • differentiation through cytokine signaling pathways at the time of activation
• After T-cell activation, activated cells migrate to the periphery where
  • killer T-cells identify infected cells and release toxic substances
• helper T-cells undergo further differentiation into subtypes

Three Signal Hypothesis

• Antigen presenting cells interact with naive T-cells in secondary lymphoid organs where
  • they allow T-cells to recognize their ingested antigens
  • they provide costimulatory input
• T-cells require all signals to be present in order to activate
• T-cells will undergo apoptosis or become anergic (state of inactivity) if
  • they receive only one of the activation signals so that
    • autoreactive cells can be removed
    • benign materials are not mistakenly recognized as harmful
• they receive signals that the infection is cured and inflammation has subsided

Feature	Signal 1	Signal 2	Signal 3
Function	Leverage specificity of T-cell receptors to detect antigenEnsure binding to antigen presenting cell with antigen of interest	Distinguish between erroneous binding of T-cell receptors and real pathogenic recognitionEnsure that the recognized antigen is on an activated antigen presenting cell	Convey information about the surrounding environment of the activation siteEnsure proper differentiation of the activated T-cells
Interacting proteins	Antigen bound to MHC type I or II proteins T-cell receptorCD4 or CD8	B7 (CD80 and CD86) that are only expressed on activated antigen presenting cellsCD28	IL-2 (T-cell survival signal) Diverse cytokinesCytokine receptors
Associations	Super antigens can artificially induce binding of T-cell receptor with MHC	Induced anergy or apoptosis if not present in conjuction with signal 1	Killer T-cells require cytokine help from helper T-cells to activate

Helper T-Cell Differentiation

• After activation, helper T-cells further differentiate in response to
  • cytokine signals released by the innate immune system
  • the inflammatory environment of the activation site
  • cross talk with other adaptive cells such as regulatory T-cells
• Each helper T-cell subtype differs in several ways including
  • general function of the class
  • signals (usually cytokines) required for differentiation
• secreted factors produced

Feature	Th1	Th2	Th17
Function	Promote cell based immunityActivate macrophages and cytotoxic T-cells	Promotes humoral immunityRecruits eosinophils as part of parasite defence	Activate neutrophils
Differentiation	IFN-γIL-12	IL-2IL-4	IL-6TGF-β
Associations	Granuloma formation Tuberculous leprosy	Lepromatous leprosyIgE production by B cells	Chronic inflammatory conditions
Secreted Factors	IFN-γIL-2	IL-4IL-5IL-13	IL-17IL-21

T-cell activation is a critical process in the immune response that allows T cells to recognize and respond to antigens, coordinating immune reactions against infections, cancers, and other threats. Understanding T-cell activation is essential for medical professionals, particularly those in immunology, infectious diseases, oncology, and transplantation. This article provides a comprehensive overview of T-cell activation, including its types, function, related studies, treatment considerations, and clinical significance.

Types of T-Cell Activation:

1. Antigen-Presenting Cells (APCs): Dendritic cells, macrophages, and B cells serve as APCs that capture antigens and present them on their cell surface using major histocompatibility complex (MHC) molecules.
2. T-Cell Receptor (TCR) Recognition: T-cell activation begins with the recognition of antigen-MHC complexes by the TCR on the surface of T cells.

Steps of T-Cell Activation:

1. Antigen Recognition: The TCR binds to the antigen-MHC complex presented by an APC.
2. Co-stimulation: Co-stimulatory molecules, such as CD28 on T cells and CD80/86 on APCs, provide additional signals for T-cell activation.
3. Signal Transduction: TCR engagement triggers intracellular signaling cascades, leading to activation of T cells.
4. Clonal Expansion: Activated T cells undergo clonal expansion, resulting in an increased number of T cells with specificity for the antigen.
5. Differentiation: Some activated T cells differentiate into effector T cells with specific functions, such as cytotoxic T cells or helper T cells.

Function of T-Cell Activation:

T-cell activation plays a pivotal role in adaptive immunity:

1. Cytotoxic T Cells: Activated cytotoxic T cells target and kill infected or cancerous cells.
2. Helper T Cells: Activated helper T cells release cytokines that modulate immune responses and support other immune cells.

Clinical Significance:

1. Infections: Impaired T-cell activation can lead to inadequate immune responses against infections, including viral, bacterial, and fungal pathogens.
2. Cancer: T-cell activation is crucial for recognizing and eliminating cancer cells through cytotoxic mechanisms.

T-Cell Activation Studies:

1. Molecular Mechanisms: Research delves into the intracellular signaling pathways that regulate T-cell activation.
2. Antigen Presentation: Studies explore how antigens are processed and presented on APCs to initiate T-cell activation.

Treatment Considerations:

1. Immunotherapy: Cancer immunotherapies, such as checkpoint inhibitors and CAR-T cell therapy, harness T-cell activation to target and eliminate cancer cells.
2. Vaccine Development: Understanding T-cell activation guides the design of vaccines to stimulate effective immune responses.

Future Directions:

1. Personalized Immunotherapy: Research focuses on individualized approaches to enhance T-cell activation in specific diseases.
2. Immunomodulation: Advancements in immunomodulatory therapies aim to regulate T-cell activation in autoimmune disorders and transplantation.

Conclusion:

T-cell activation is a complex process that initiates immune responses against infections and cancers. Recognition of antigens presented by APCs triggers intracellular signaling pathways, leading to T-cell activation, clonal expansion, and differentiation into effector cells. This process is crucial for coordinating adaptive immune responses and ensuring immune system efficacy. T-cell activation has significant clinical implications for infections, cancer, and immunotherapy.

Check out Interview Preparation, CV and Personal Statement Editing – The Finale.