Immunological Memory and Adaptive Immune System

Immunological Memory

This lecture focuses on immunological memory, a key feature of the adaptive immune system. It covers the differences between innate and adaptive immunity, the generation of memory responses (primarily B cell memory), and the importance of memory in vaccination.

Key Concepts

• Adaptive vs. Innate Immunity:
  • Adaptive immune system exhibits memory; innate immune system generally does not (though some debate exists regarding NK cells).
• Importance of Memory:
  • Basis of vaccination.
  • Allows the immune system to remember prior encounters with pathogens, providing protection upon re-exposure.

The Adaptive Immune Response and Memory

Primary Response

1. Activation: T and B cells are activated by an antigen.
2. Clonal Expansion: T and B cells undergo clonal expansion, creating many copies of cells specific to the encountered pathogen.
3. Differentiation: Cells differentiate into effector cells.
4. Pathogen Clearance: Ideally, the pathogen is cleared from the system.

Memory Formation

• A population of memory cells remains after the pathogen is cleared.
• These cells enable a faster, stronger response upon subsequent exposure.

Secondary Response

• If the same pathogen re-enters the system:
  • Memory cells respond more vigorously.
  • The magnitude of the response is greater than the primary response.
  • The response time is much shorter (1-2 days versus 5-10 days).
  • Pathogen control is achieved more rapidly.

Vaccination

• Vaccination exposes the adaptive immune system to antigens from a pathogen.
• This leads to the generation of memory cells, providing protection against future infection by the same pathogen.

Characteristics of Memory

• Tenacity: Memory cells can differentiate into effector cells upon re-exposure to the antigen.
• Longevity: Memory cells can persist for decades.
• Robustness: Memory cells provide a rapid and effective defense upon re-encounter with the pathogen.

B Cell Memory

• B cell memory is a feature of T cell-dependent responses.
• T cell-independent responses (e.g., IgM production against polysaccharide antigens) do not typically generate strong memory.

B Cell Response Process

1. Activation: B cells are activated by a pathogen.
2. Proliferation: Activated B cells proliferate and differentiate into antibody-producing cells.
3. Antibody Production: Early response involves IgM production.
4. Isotype Switching: Over time, B cells switch to producing other antibody isotypes (e.g., IgG, IgA).
5. Affinity Maturation: B cells undergo affinity maturation in germinal centers to produce higher-quality antibodies.
6. Plasma and Memory Cell Generation: The process generates both long-lived plasma cells and memory B cells.

T Cell-Independent vs. T Cell-Dependent B Cell Responses

T Cell-Independent

• B cells can produce IgM antibodies without T cell help.
• Often against polysaccharide antigens, which can crosslink multiple B cell receptors.
  • Example: Antibodies against ABO blood group antigens are IgM.

T Cell-Dependent

• B cells require T cell help to produce higher-quality antibodies (isotype switching).
• T cell help is typically required for protein antigens.
• T cells recognize protein antigens presented on MHC molecules.
• T cell and B cell responses must be specific to the same antigen for effective help to occur.

T Cell Help for B Cells

• Helper T cells (CD4+ T cells) provide help to B cells.

Mechanism

1. Activation in Lymph Nodes: T and B cells are activated in draining lymph nodes.
2. Migration: Activated T and B cells migrate towards each other.
   • B cells move towards the T cell zone.
   • T cells move towards the B cell zone.
3. Interaction at the T-B Border: T cells and B cells interact at the border between the T cell and B cell zones.
4. CD40-CD40L Interaction: Crucial interaction between CD40L on T cells and CD40 on B cells.
   • Triggers B cell activation and isotype switching.
5. Cytokine Production: Helper T cells produce cytokines that direct B cell isotype switching. Examples:
   • TGF-β: Promotes IgA production (important for mucosal immunity).
   • IL-4: Promotes IgE production (important for helminth infections).
   • Interferon-γ: Promotes IgG production (important for viral and intracellular infections).

Importance of Isotype Switching

• Different antibody isotypes have different functions.
  • IgA: Protects mucosal surfaces.
  • IgG, IgE, etc: Different functions (covered in a separate lecture).
  • IgM: Good at fixing complements.

Affinity Maturation

• Process of improving the quality (affinity) of antibodies.
  • Essential for memory responses.
• Affinity = measure of how well the antibody binds to the antigen.
  • High affinity is desirable for effective protection.

Somatic Hypermutation

• Molecular process that fine-tunes antibody affinity.
• Mutations are introduced in the antigen-binding part of the antibody (VDJ recombination).

Germinal Centers

• Specialized microstructures in lymph nodes where affinity maturation occurs.
• B cells that have received T cell help migrate back into the B cell follicle and start proliferating.
• Lymph node cross-sections reveal:
  • Dark Zone: Area of intense B cell proliferation and somatic hypermutation.
  • Light Zone: Area where selection of high-affinity B cells occurs.

Selection Process in the Light Zone

1. Follicular Dendritic Cells (FDCs): Display antigens to B cells.
   • FDCs are not the typical dendritic cells that present antigen to T cells; they display antigens without processing.
2. Competition: B cells compete to bind to the antigen displayed by FDCs.
3. T Follicular Helper (Tfh) Cells: Helper T cells migrate into the follicle and continue to help B cells during selection.
4. Selection of High-Affinity B Cells: B cells that bind with high affinity survive; others undergo apoptosis.

Outcome of Affinity Maturation

• Selected B cells differentiate into:
  • Memory B cells.
  • Plasma cells (which migrate to the bone marrow and produce antibodies).

Memory Specificity

• Memory is specific to the antigen encountered.
• Vaccination against one pathogen does not protect against others.

Antibody Kinetics

• Primary response: IgM early, then isotype switching to IgG, IgA, etc.
• Secondary response: Dominated by IgG (high affinity).
• Response to a different antigen: Primary response with IgM production.

T Cell Memory

• Similar kinetics to B cell responses (primary response, contraction phase, memory).

T Cell Activation

• Antigen is brought to the local lymph node by dendritic cells (conventional dendritic cells).
• T cells are activated, undergo clonal expansion, and differentiate into effector T cells.
• Memory T cells are generated.

Cytotoxic T Cells

• Early events influence whether T cells become short-lived effector cells or long-term memory cells.
• Transcription factors (e.g., TBET, EMS) play a role in this process.

Types of T Cell Memory

• Central Memory T Cells (TCM):
  • Reside in lymph nodes.
  • High capacity for proliferation.
  • High levels of stimulation (tenacity).
• Effector Memory T Cells (TEM):
  • Similar to effector cells but with longer lifespan.
• Tissue-Resident Memory T Cells (TRM):
  • Reside in tissues where they initially encountered antigen.
  • Provide long-term protection in those tissues.

Maintenance of T Cell Memory

• Does not necessarily require persistent antigen stimulation.
• Relies on cytokines such as IL-7 and IL-15 for survival.