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Innate vs. Adaptive Immunity

• Overarching theme: differentiating self from non-self.
• Both systems must act at the site of invasion/infection.
• Goal: eradicate invading pathogens before a stable infection is established.
• Innate immunity:
  • Natural, native, non-specific.
  • Broad-spectrum response.
  • Attempts to clear pathogens before establishing infection.
• Adaptive immunity:
  • Response against individual components of pathogens (down to individual proteins).
  • Capacity to remember specific pathogens.

Why Adaptive Immunity?

• Microorganisms predate animal life; co-evolution occurred.
• Animals developed mechanisms to compete with and survive alongside microorganisms.
• Adaptive immunity evolved, particularly after animals started consuming other animals, leading to exposure to new microbes.
• The innate immune system recognizes common features of pathogens, while adaptive immunity targets single proteins or even peptide sequences.
• T cells recognize specific amino acid combinations via unique receptors.

Interactions Between Innate and Adaptive Immunity

• Adaptive immunity does not function in isolation; requires interaction with innate immune cells.
• Full activation of the adaptive immune system depends on innate immune cells.
• B cell activation leads to antibody production.
• CD8+ T cell activation mediates cytotoxic (killer) T cell function.
• Helper T cells shape the adaptive immune response.
  • Directing it towards bacterial or viral infections.
• Innate immune system:
  • Fast response.
  • Recognizes pathogen presence.
  • Triggers and shapes the adaptive immune response (e.g., releasing effector molecules).
• Vaccines:
  • Aim to trigger a memory response without initial pathogen exposure.
  • Adjuvants stimulate the innate immune response to shape vaccine-induced immunity.

Adaptive Immunity Specificity

• Responds to peptides and proteins, even short peptide sequences (10-15 amino acids).
• Triggers a memory response.
• Subdivided into:
  • Humoral immunity (antibody production via B cells).
  • Cell-mediated immunity (T cell activation).
• Highly specific: each T and B cell recognizes a single type of antigen.
• Diversity achieved through many T and B cells with different receptors.
• Maintains diversity to respond to various pathogens.
• For example, possessing only T cells recognizing the SARS-CoV-2 spike protein is insufficient for protection against other viruses.

Clonal Expansion and Memory

• When a T cell is activated:
  • Proliferates, duplicating itself.
  • Increases in number.
  • Forms memory cells.
• Second exposure leads to a rapid and specific response due to a higher number of antigen-recognizing T cells.

Innate vs. Adaptive Immunity - Specificity and Diversity

• Adaptive immune cells specific to antigens within microbes and non-microbial antigens.
• Innate immunity has limited diversity, recognizing classes of pathogens.
• Adaptive immunity has immense diversity due to unique receptors on T and B cells, generated through gene combinations.

Adaptive Immunity - Memory and Response

• Memory response formation.
• Elimination of self-reactive immune cells during T and B cell development.
• Lymphocytes travel to the site of infection.
• Antibodies secreted; blood proteins include antibodies and T/B cells.

Antigen Presentation

• Focus: Activating T cells.
• How T cells recognize antigens.
• What happens when T cells are activated.
• This lecture: antigen-presenting cells.
• Discussing: Major Histocompatibility Complex (MHC) I and II.

Antigen Specificity

• Antigen: Any substance that induces an immune response (toxin, foreign substance, or even self-protein in autoimmunity).
• Specificity: Ability to bind one, not another member of the same family.
• Analogy: Key (antigen) fitting a specific lock (receptor) on a door.

Clonal Selection Theory (McFarlane Burnett)

• Explains diversity and specificity in the immune system.
• Collection of cells recognizing different things (even single amino acids).
• Activation selects a clone specific to an antigen, allowing it to expand.
• Each adaptive immune cell expresses a unique receptor, enabling diverse immune responses.
• Holds true for both B and T cells.

Generating Diversity

• The gene encoding the B cell receptor has multiple versions.
• Diversity achieved through combinations of gene components.
• Genes for the B cell receptor:
  • One variable (V) gene.
  • One diversity (D) gene.
  • One joining (J) gene.
  • Constant region.
• Example: 20 V genes, 15 D genes, 75 J genes can create many combinations (e.g., V1 + D4 + J5).
• Receptor chains: heavy and light chains with VDJ combinations.
• Generates approximately $10^8$ potential B cell combinations.
• T cells: around $10^{12}$ different types.
• Binding occurs where genes combine; variability needed only in the protein-binding region.
• The constant region provides function.
• T cells: leader sequence, variable, diversity, and joining regions (BDJ combinations).
• T cell receptor: alpha and beta chains with those combinations.

Epitopes

• B and T cells recognize proteins and peptides.
• Epitope: Specific region on a protein or peptide recognized by the B or T cell receptor.
• B cells recognize epitopes within an entire protein.
• There are a multitude of different epitopes on any given protein.
• T cells recognize peptide sequences.
• T cells only see the peptide if another protein holds it on its surface via the Major Histocompatibility Complex.

Antigen Presentation

• Large proteins are broken down into small peptide components for T cell recognition.
• Peptides are loaded onto MHC molecules and expressed on the cell surface.
• Antigens:
  • Endogenous: arise within the cell (e.g., viral proteins).
  • Exogenous: come from outside the cell.

Major Histocompatibility Complex (MHC)

• Presents peptide to T cells.
• Diversity through polymorphism between MHC molecules.
• Each individual expresses many types/versions of MHC genes.
• Diversity enhances survival (more peptides can bind).
• MHC constantly synthesized and expressed on cell surface.
• Incorporates antigens and presents them to T cells (antigen-MHC complex).

MHC Class I and II

• Both present peptides to T cells but to different types.
• MHC Class I:
  • Presents proteins from inside the cell (endogenous antigens).
  • Expressed by any cell with a nucleus.
  • Activates CD8+ T cells (killer T cells targeting virus-infected cells).
  • Viruses need the nucleus to make protein, these cells need to be killed.
• MHC Class II:
  • Activates CD4+ T cells (shape the adaptive immune response).
  • Expressed only by professional antigen-presenting cells (APCs).
  • APCs can take up, process, and present proteins from outside the cell.

Professional Antigen-Presenting Cells (APCs)

• Dendritic cells, macrophages.
• B cells express MHC Class II to activate CD4+ T cells for their own activation.
• Dendritic cells and macrophages are phagocytic (via phagocytosis, macropinocytosis, endocytosis).
• APCs must find naive T cells (which reside in the circulatory/lymphatic systems, not tissues).
• APCs (macrophages, dendritic cells) survey tissues, activated by innate stimulation.
• Activated APCs migrate to the draining lymph node to find naive T and B cells.

Lymph Nodes

• Bring together APCs and lymphocytes in a controlled environment.
• Filter extracellular fluids, surveilling for antigens.
• Lymphocytes arrive via the circulatory system; antigens via lymphatic vessels.
• Promotes adaptive immune response activation.
• Lymph node serves the purpose of providing the naive cell with the antigen.
• Lymph node removal can be problematic due to impaired infection drainage.
• Vaccinations cause lymph node expansion.

T Cell Receptor and MHC Binding

• T cell receptor has alpha and beta chains.
• Accessory molecules (CD4 or CD8) dictate MHC binding.
• CD4 binds to MHC Class II; CD8 binds to MHC Class I.
• MHC Class II: alpha 1, alpha 2 chain and beta 1, beta 2 chain.
• The peptide is presented within a cleft of the MHC molecule.
• Peptide sits in a cleft of the MHC molecule.

MHC Genes

• Polymorphic: many variants of the gene at a population level.
• Heterozygous: individuals express multiple copies of the allele.
• Co-expressed: every single copy of the gene is expressed.
• Polygenic: multiple copies of the genes are expressed.
• Human Leukocyte Antigen (HLA) locus.
• There is huge diversity in the number of MHC genes present within cells.
  Reason to have a Complicated MHC.
• Being able to recognize a variety of pathogens.

MHC Restriction (Doherty and Zinkernagel)

• T cells are specific to their antigen and the MHC presenting the antigen.
• T cells from virus-infected mice protected other mice of the same strain but not different strains.
• T cells must match the MHC to activate CD8+ T cells for pathogen clearance.
• Correct combination of T cell receptor and MHC is required.
• T cell receptor must be educated against its MHC.

MHC Peptide-Binding Preference

• MHC molecules have a preference for particular types of amino acids.
• MHC binding is quite specific.
• An example is the MHC molecule H-2Kb from black sex mice which binds the Symfecal peptide from chicken eggs.

MHC Diversity and Survival

• Having different MHCs to bind a huge variety of peptides improves immune cell reactivity.
• Species with low MHC diversity are susceptible to infections.
• Diversity ensures that populations can respond to a range of threats.
• Heterozygous genotypes show greater survival rates.

Partner Selection Based on MHC

• MHC diversity is surprisingly linked to attractiveness; diversity MHC implies finding someone who has highly diverse MHC.
• Females prefer scents of individuals with diverse MHCs, potentially improving offspring survival.

Lecture Summary

• Lymphocytes express clonally unique receptors to recognize specific antigens.
• B cells recognize regions on proteins; T cells recognize small peptide sequences.
• Endogenous antigens come from within the cell and are presented by MHC Class I to CD8+ T cells. Exogenous antigens come from outside the cell.
• Antigen-presenting cells express peptides on MHC Class II molecules, activating CD4+ T cells.
• MHC molecules are highly polymorphic and polygenic, adding diversity to the immune system to respond to a huge variety of potential pathogens.
• MHC diversity improves survival and can influence attractiveness to the opposite species to enhance offspring outcomes.