LEC5: Study Notes on Immune Response and Activation Mechanisms

Introduction to Immune Response

The initial decision in an immune response is whether to respond to an infiltrating pathogen or not. Once activated, the immune response can be difficult to halt. Therefore, it is crucial to activate responses strictly against pathogens while avoiding activation against benign entities such as pollen or self-antigens. Today's lecture will cover the connection between antigen specificity and the detectability of danger, ensuring that only pathogen-specific T and B cells are activated, without inadvertently activating those that recognize self or food. While T and B cells are powerful weapons against pathogens, their uncontrolled activation can lead to detrimental autoimmune responses.

T and B Cell Specificity

Each T and B cell contains a unique receptor that recognizes a specific epitope or antigen. The diversity of these receptors arises from somatic recombination involving Variable (V), Diversity (D), and Joining (J) gene segments. The selection of a random V segment, J segment, and, in some cases, a D segment results in an immense variety of receptors. Additionally, junctional diversity introduces further mutations at the junction sites during recombination, increasing receptor diversity.

  • Permanent Changes: These modifications are permanent and irreversible, resulting in a stable receptor that will remain with the cell throughout its life. Consequently, an expansive and diverse set of T and B cells develops, enabling recognition of nearly any potential challenge.

  • Clonal Expansion: When a pathogen is encountered, specific T and B cells will undergo clonal expansion, multiplying to effective levels to contribute to the immune response. The high specificity of these cells enhances response efficiency, while their ability to discern between self and non-self remains a critical caveat.

Activation of T Cells

T and B cells are not initially knowledgeable about what they recognize. Their activation relies on successful recognition of specific antigens without discernment regarding self versus non-self origins. Warning: inappropriate activation can be hazardous.

  • Self-Reactive T Cells: Self-reactive T cells circulate in the body post-development, as the final stages of selection are not flawless. Activation of these self-reactive T cells can lead to autoimmune issues; however, they remain harmless as long as they are not activated inappropriately.

Innate Immune System and Danger Recognition

In contrast, innate immune cells (such as macrophages) utilize pattern recognition receptors (PRRs) designed to detect "danger," thereby identifying damaged cells or the presence of pathogens. These PRRs recognize conserved molecular patterns absent from host tissues, allowing innate cells to differentiate between pathogen-associated antigen and self-antigen.
Thus, innate immune cells assist adaptive immune responses by determining whether an infection is present.

Antigen Presentation

Crucially, T cells do not recognize antigens independently.

  • Antigen Presenting Cells (APCs): Antigen-presenting cells such as dendritic cells, macrophages, and B cells play a vital role in presenting antigens to T cells. When an APC detects a pathogen using PRRs, it internalizes and processes the pathogen, slicing it into 25-amino acid peptides that can be presented to T cells. This feat is akin to a “precision handshake” in immune signaling, ensuring specificity in T cell activation.

  • Role of Dendritic Cells: Dendritic cells are pivotal in activating naïve T cells post-phagocytosis. Once they detect pathogens, they cease random sampling and migrate to the lymph nodes, where they present collected antigens.

Major Histocompatibility Complex (MHC)

MHC molecules facilitate the presentation of antigens.

  • MHC Class I and Class II: MHC class I is located on all nucleated cells, presenting primarily intracellular antigens to CD8 cytotoxic T cells. MHC class II is expressed exclusively by professional APCs, presenting extracellular peptides to CD4 T helper cells.

    • Peptide Binding: MHC class I can present shorter peptides (7-11 amino acids) with ends closed, while MHC class II can present longer peptides with open ends. The T cell receptor (TCR) must simultaneously recognize both the MHC molecule and the peptide bound to it for effective activation; single recognition is insufficient.

  • Diversity and Polymorphism of MHC: MHC molecules exhibit significant polymorphism with 5000 alleles in the human population. MHC haplotypes can differ substantially among individuals. This genetic diversity enhances the immune system’s ability to respond to a wide range of pathogens but complicates organ transplants due to potential graft-versus-host complications.

T Cell Activation

Each T cell recognizes a specific antigen presented by MHC, with the requirement for a second signal for full activation.

  • Two-Signal Hypothesis: The first signal occurs when the T cell receptor interacts with the MHC-peptide combination, establishing specificity; however, this does not guarantee activation due to the absence of danger recognition. The second signal is mediated through costimulatory molecules. CD28 on T cells binds to CD80/CD86 on APCs when danger is recognized, thus promoting T cell activation.

    • Without this second signal, T cells may undergo anergy (deactivation) or apoptosis.

B Cell Activation and Helper T Cells

B cells can independently recognize native antigens via their surface immunoglobulin receptors but require assistance from T cells for full activation via T-dependent mechanisms.

  • T-Dependent and T-Independent Responses: T-dependent responses occur primarily with protein antigens, relying on T cell help for isotype switching and affinity maturation, while T-independent responses arise in the presence of carbohydrate antigens without T cell help, leading to limited functionality.

  • Role of B Cells: B cells present processed peptides that match T cell recognition after internalizing and degrading antigens. If a T cell recognizes the peptide from a B cell, the B cell may receive activation signals, confirming that it recognizes the same pathogen, hence allowing the B cell to participate in the immune response.

Memory Response and Regulation

Following initial infection, memory T and B cells are formed, expediting responses to subsequent exposures to the same pathogen.

  • Less Stringent Activation for Memory Cells: Memory T cells require weaker interaction signals to activate, as they can often bypass the need for signal two altogether. Memory B cells, having undergone affinity maturation, can more swiftly engage in antigen recall.

  • Resolution of Immune Response: As the pathogen is cleared, innate cells cease presentations, T and B cells lose stimulation, intrinsically leading to immune response resolution. Cytokines such as IL-10 down-regulate T cell activity, while the majority of T cells die, transitioning back to a resting state, with some differentiating into memory cells.

Conclusion and Recommended Reading

In summary, the innate immune system detects initial infections and communicates with adaptive immune components to activate them appropriately. The lecture promotes understanding the critical balance between specificity and response within the immune system. For further study, it would be beneficial to reference Abbott’s Basic Immunology, Chapter 5, for a comprehensive overview and review questions.