CD4+ T Cells and Class II MHC — Comprehensive Study Notes

Page 1 — The Role of CD4+ T Cells in Immune Defenses

  • CD4+ T cells play multiple roles in host defenses against infection.
  • Two types of infection require that CD4+ T cells are activated:
    • Intravesicular/intravacuolar (within phagocytes)
    • Extracellular
  • In both cases, antigen presentation using Class II MHC molecules is required to activate CD4+ T cells.
  • Antigen processing begins with antigens taken up and processed in acidified endosomes containing many proteases, resulting in cutting the protein into peptide fragments.

Page 2 — Processing and Presentation of Antigens to CD4+ T Cells

  • Endosomes containing peptide fragments fuse with vesicles containing specialized host Class II MHC presentation proteins, allowing complexes to form.
  • Class II MHC (MHC II) are from the ER during synthesis; antigen peptides are loaded in endosomal compartments.
  • Antigen peptides expressed only by “professional” APCs: Macrophages, Dendritic cells, B cells (compare to Class I MHC expression).
  • Complexes are shuttled to the surface. Peptides that reach the surface will be available for stimulating T cells.

Page 3 — Map of the Human MHC and Class II MHC Allelic Variations

  • Structure features include Transmembrane Segments and Cytoplasmic Segments for the Class II MHC heterodimer (α and β chains).
  • 3 isoforms of human Class II MHC: DP, DQ, DR.
  • The α1/β1 and α2 domains form the peptide-binding site; the walls are α-helices and the floor is a β-sheet.
  • Allelic variation is high: hundreds of polymorphic structures among the human population (Class II is highly polymorphic; Class I has different patterns).
  • Humans are diploid, so the maximum number of different Class II MHC molecules in an individual is extmax=8=4imes2.ext{max} = 8 = 4 imes 2.
  • Alleles are co-dominantly expressed, with very low frequency of recombination (examples: DRα/DRβ; DPα/DPβ; DQα/DQβ; DRα/DRβ).
  • The number can be less if there is homozygosity for any isoform.

Page 4 — How Class II MHC Molecules Determine the Specificity of T Cells That Are Activated

  • Class II MHC is a heterodimer with a peptide-binding site formed by α1 and β1 domains; and α2 domains contribute to structure.
  • External domains: 4 external domains cover the peptide-binding site.
  • 3 isoforms: DP, DQ, DR.
  • The α1 domain and β1 domain form the peptide-binding groove; alpha helices (walls) and beta-sheet (floor) define the binding pocket.
  • Particular amino acid positions are highly variable from one allele to another, creating a polymorphic set of Class II MHC molecules.
  • Peptide Binding Specificity of Class II MHC is determined by how peptides fit into this groove.

Page 5 — What Qualities of an Antigen Peptide Allow Optimal Binding to Class II MHC?

  • Antigen peptides that bind Class II MHC are generally 15–25 amino acids in length, enabling enough contacts within the binding groove.
  • The Anchor Residues are contact points with polymorphic MHC residues at the bottom/floor of the binding site.
  • The exact collection of anchor residues in an antigen peptide is referred to as its PEPTIDE-BINDING MOTIF.
  • The anchor residues determine how well a given peptide binds to a particular MHC II allele, contributing to specificity.

Page 6 — Peptide Anchor Residues and TCR Recognition

  • Peptide anchor residues bind polymorphic MHC residues at the bottom (floor) of the binding site.
  • TCR binds to MHC residues of the α-helical walls and residues of the antigen peptide in the groove.
  • TCR-MHC recognition is MHC-restricted, providing Signal 1 of T cell activation when the peptide/MHC complex is engaged by the TCR.
  • The purpose of binding antigen peptide/MHC complexes to the TCR is to provide Signal 1 in the two-signal process of T cell activation.
  • Co-receptors CD4 and CD8 assist this process.
  • CD4 co-receptor Provides:
    • Stabilization of TCR binding to the MHC/peptide complex.
    • Selective activation of T cells with appropriate effector function.
  • CD4 is expressed on approximately 60ext−70extextpercent60 ext{-}70 ext{ extpercent} of T cells in blood.
  • CD4 binds a conserved (non-polymorphic) region of Class II MHC molecules.

Page 7 — APC-CD4+ T Cell Interaction and Co-stimulation

  • Immunological synapse arrangement: APC presents Class II MHC to TCR on CD4+ T cell with CD4, CD3 complex involved.
  • Signal 2 is delivered when co-stimulatory molecules are engaged: APC expresses B7 (CD80/86) binding to CD28 on T cells.
  • This co-stimulation triggers intracellular signaling pathways leading to gene activation.
  • Visual: APC — CD4+ T Cell — Class II MHC — TCR — CD4 — CD3 Complex.
  • Warning: What’s missing in the simplified view is CD3 signaling components and their role in TCR signaling.

Page 8 — Interleukin-2 and CD4+ T Cell Subsets

  • Interleukin-2 (IL-2) is the main T cell growth factor: signals to maintain growth and to steer/fine-tune effector functions.
  • Growth and differentiation signals for CD4+ T cells are provided via cytokines.
  • Subsets of CD4+ T cells are distinguished by the cytokines they produce and their target cells.
  • TH1 cells: produce IL-2, IFN-γ, TNF-α → primarily act on macrophages.
  • TH17 cells: produce IL-17 → target neutrophils.
  • TH2 cells: produce IL-4, IL-5, IL-6, IL-10, TGF-β → target B cells.
  • TFH (T follicular helper) cells: produce IL-4, IL-21 → target B cells.
  • T regulatory cells (TREG): produce TGF-β, IL-10, IL-4 → regulatory/inhibitory effects.
  • In general: CD4+ T cells are distinguished by cytokine production and cellular targets.

Page 9 — Why Do We Need Multiple CD4+ T Cell Kinds?

  • Inflammatory T cells include TH1 and TH17; Helper T cells include TFH; and B cell help is coordinated by TH2/TFH.
  • CD4+ T cell effector functions include antagonistic and complementary roles across different subsets.
  • TH1/TH17 (Inflammatory) help eliminate intracellular pathogens and promote innate inflammation and cell-mediated immunity (CMI).
  • TH2 and TFH help activate B cells and promote antibody production for extracellular pathogens.

Page 10 — Inflammatory T Cells and Their Role in Infections

  • Inflammatory T cells (TH1 and TH17) function to enhance innate inflammation and CMI.
  • TH2 cells are more aligned with extracellular infection and antibody responses.
  • Some phagocytosed microbial pathogens may survive digestion inside endosomes and may be resistant to destruction.
  • Destruction of a pathogen may be enhanced by cytokines produced by TH1 and TH17 CD4+ T cells.
  • Endosome-resident pathogens can be affected by inflammatory cytokines that augment destruction.

Page 11 — TH1 Cells and Macrophage Activation

  • CD4+ TH1 cells (Inflammatory T cells) potentiate MACROPHAGE ACTIVATION:
    • Increase phagocytosis-related activities.
    • Increase levels of Class I and II MHC.
    • Increase cytokines (e.g., TNF, IL-1, IL-6, IL-8, IL-12).
  • TH1 cells produce pro-inflammatory cytokines: IL-2 and IFN-γ.
  • Macrophage activation is enhanced by TH1 cell binding through CD40-CD40L (CD154).
  • TH1 responses also promote increased vascular permeability and direct cytotoxic effects, and help activate the acute phase response (fever).
  • There are macrophage subsets:
    • M1 pro-inflammatory macrophages (IFN-γ–activated) promote CD4+ TH1 functions.
    • M2 repair macrophages produce anti-inflammatory cytokines IL-10 and TGF-β and are important during wound repair.

Page 12 — TH17 Cells and Macrophage/Neutrophil Interactions

  • TH17 cells induce chemokines that recruit and activate neutrophils.
  • TH17 cells induce IL-6, which stimulates production of acute phase proteins.
  • TH17 cells synergize with IFN-γ, TNF-α, and IL-1β to amplify inflammatory responses.
  • TH17 cells produce the pro-inflammatory cytokine IL-17.
  • Neutrophil activities are enhanced by TH17 cells.

Page 13 — Other Contributors: NKT Cells and Regulatory T Cells

  • NKT Cells:
    • Express α/β TCR with limited specificity for lipid antigens presented by CD1d on APCs.
    • Can produce IFN-γ, IL-4, GM-CSF, and other cytokines/chemokines (e.g., IL-2, IL-13, IL-17, IL-21, TNF-α).
    • Play roles in activating numerous cell types; immunosuppression may be required to avoid excessive inflammation.
  • This context leads to Regulatory T cells (Treg) as part of immune regulation.

Page 14 — TH1, TH17, APCs, TReg, and CD4 Class II MHC Interactions

  • Diagrammatic relationships: TH1, TH17, APCs, TReg, CD4, Class II MHC, TCR, co-stimulatory molecules.
  • Cytokine milieu: IL-4, IL-10, TGF-β; Tregs express CD25high and foxP3+.
  • When antibody-based defense is required, B cell activation and antibody production play a central role against extracellular microbial pathogens.
  • The helper T cell role in extracellular pathogens involves interactions that shape antibody responses.

Page 15 — Exogenous Antigen Processing and B Cell Help Mechanisms

  • The Mechanism: Exogenous antigen processing for extracellular infection.
  • The Strategy: Process antigen so that T cells with specialized B cell helper activity are activated.
  • CD4+ TH2 and TFH cells are the helpers of B cells.
  • They can produce TH1-inhibitory cytokines, such as IL-10 and TGF-β.
  • TH2/TFH express co-stimulatory CD40L (CD154), which is required for effective B cell activation, antibody class switching, and antibody affinity maturation.
  • Produce B cell growth-promoting cytokines (e.g., IL-4, IL-5).
  • B lymphocytes differentiate into plasma cells that produce antibodies.
  • The cascade includes Antigen, Antibody, Immunity; Helper T cells contribute to Antigen clonal expansion via CD40-CD40L interactions.

Page 16 — End of Transcript

  • (No additional content provided beyond numbering; summary concludes with mechanisms of CD4+ T cell help in extracellular infection.)

Key formulas and numeric references to remember

  • Maximum Class II MHC diversity per individual: extmax=8=4imes2.ext{max} = 8 = 4 imes 2.
  • CD4+ T cells in blood: approximately 60ext−70extextpercent60 ext{-}70 ext{ extpercent} of T cells.
  • Peptide length for Class II binding: 15extto2515 ext{ to } 25 amino acids.
  • Co-stimulation: Signal 2 is provided by B7-CD28 interactions on APCs and T cells, respectively.
  • Signal 1 is TCR recognition of peptide/MHC complexes (MHC-restricted recognition).
  • TH1 cytokines: IL-2, IFN-γ, TNF-α.
  • TH17 cytokine: IL-17.
  • TH2 cytokines: IL-4, IL-5, IL-6, IL-10, TGF-β.
  • TFH cytokines: IL-4, IL-21.
  • Treg cytokines: TGF-β, IL-10, IL-4.
  • Macrophage subsets: M1 (IFN-γ–activated, pro-inflammatory) and M2 (producing IL-10, TGF-β, involved in wound repair).