Antigen Presentation to Lymphocytes

Antigen Capture and Presentation to Lymphocytes

• Lymphocytes recognize peptides bound to MHC molecules on antigen-presenting cells (APCs)
• Key study points include: how rare naive lymphocytes find microbes specifically and how different types of T cells recognize microbes in different cellular compartments
• APC's (e.g., dendritic cells) capture antigens and present them on MHC molecules
• MHC molecules display peptide antigens to T cells, triggering an immune response

Antigens Recognized by T-Lymphocytes

• The majority of T lymphocytes recognize peptide antigens bound to MHC molecules of APCs
• T cells contact a residue of peptide
• Polymorphic residue of MHC
• Anchor residue of peptide
• "Pocket" of MHC
• Peptide

Capture and Display of Microbial Antigens

• Microbes are captured by lymphatic vessels and connective tissue and travel to lymph nodes
• Antigens enter the blood stream via venules
• Antigens are captured by antigen-presenting cells in the spleen
• Antigen presentation occurs in the lymph nodes, and spleen
• Different types of dendritic cells (classical and plasmacytoid) play critical roles in capturing and presenting antigens
• Selected surface markers (human)
• CD11c, BDCA2 (CD303), BDCA1 (CD1c), Dectin
• TLRs 4, 5, 8, and TLRs 7, 9
• Major cytokines expressed
• TNF, IL-6, IL-12, IL-23 , Type I interferons

Antigen Uptake, Maturation, and Migration of Dendritic Cells

• Dendritic cells (DCs) express Pattern Recognition Receptors (PRRs), including Toll-like receptors (TLRs) and C-type lectin receptors (CLRs)
• DC maturation occurs upon pathogen recognition or cytokine signaling (like TNF, IL-1)
• Maturation markers include CD40, CD80, and CD86
• Loss of adhesiveness
• Expression of chemokine receptor (CCR7)
• Migration to lymphoid organs to present antigens
• Increase in MHC class II expression

Major Histocompatibility Complex (MHC)

• MHC (HLA) is a genetic locus that determines tissue graft acceptance or rejection
• Codes for membrane proteins on antigen-presenting cells
• Code for the transporter associated peptide (TAP)
• MHC III contain genes for complement C2, C4, factor B and cytokines
• HLA system is the most polymorphic gene system in humans
• Thousands of alleles
• Each person has two HLA alleles of each type (haplotype)

Structure of MHC Molecules

• Class I MHC:
• Consists of a chain non-covalently associated with β2-microglobulin
• a domain consisting of two walls and an amino acid peptide-binding cleft
• Peptide-binding cleft floor amino acids bind peptides
• The wall makes contact with TCR
• MHC-I polymorphism occurs mostly in the alpha chain amino acid residue
• α3 domain is invariant and contains a site that binds the CD8 coreceptor
• Class II MHC:
• Consists of two transmembrane chains (α2 and β2)
• Amino-terminal regions of both chains (α1 and β1 domains) contain polymorphic residues and form a cleft
• β2 domains contain the binding site for the CD4 T cell co-receptor

Properties of Major Histocompatibility Complex (MHC) Molecules and Genes

• Located on the short arm of chromosome 6
• Each person inherits one HLA class I gene (A, B, C) from each parent
• Each person inherits two HLA class II genes (DP, DQ) encoding for the alpha chain and beta chain from each parent
• Each HLA allele is given by a numeric designation (e.g., HLA-A2, B5, DR3, etc.)

Antigen Capture and Presentation to Lymphocytes (continued)

• Reactions of MHC molecules:
• May be involved in reactions of T cells to nonpeptide antigens (e.g., small molecules or metal ions)
• Class I MHC proteins (A, B, and C) present intracellular antigens (e.g., from viruses or tumors) to cytotoxic T lymphocytes
• MHC class II proteins (DR, DQ, and DP) present extracellular antigens to T helper cells
• A single T cell only needs to recognize a peptide displayed on 0.1% to 1% of the approximately 10⁵ MHC molecules on the surface of an APC
• MHC molecules cannot discriminate between self and foreign antigens
• T cells specific for self-antigens are killed or inactivated

Clinical Significance of MHC

• Important in tissue transplant procedures
• MHC classes I and II can induce graft rejection
• Certain HLA types appear to play a role in autoimmune diseases

Association of HLA Alleles and Disease

• Various diseases, such as ankylosing spondylitis, celiac disease, rheumatoid arthritis, and type 1 diabetes, have associations with specific HLA alleles.

Class I MHC Pathway of Processing of Cytosolic Antigens

• Cytosolic proteins (unfolded and tagged with ubiquitin) are degraded into peptides by the proteasome
• Transporter associated with antigen processing (TAP) transports peptides into the endoplasmic reticulum (ER)
• TAP pumps peptides into the ER
• Chaperone (like Tapasin) stabilizes newly synthesized class I MHC molecules in the ER by attachment to TAP

Tc Recognize and Destroy Target Cells

• CD8+ T cells bind to the antigen-MHC class I complex on the target cell surface
• T cells release enzymes (e.g., perforins, granzymes) that destroy the target cell

Class II Major Histocompatibility Complex Pathway of Processing of Internalized Vesicular Antigens

• Extracellular microbes or proteins are ingested by phagocytosis
• Proteins are broken down in acidic vesicles (like endosomes or phagosomes)
• Invariant chain (Ii) binds to class II MHC molecules in the ER, directing them to endosomes
• Ii is degraded, releasing CLIP (invariant chain peptide) from the cleft
• HLA-DM exchanges CLIP with other peptides to load MHC class II molecules

Th Assist Antibody Production

• CD4+ T helper cells stimulate B cells to differentiate into antibody-producing plasma cells (secreting antibodies)

Class I MHC-Restricted Cross-Presentation

• A subset of classical dendritic cells can ingest infected host cells, dead tumor cells, microbes, and microbial antigens
• Transport antigens to the cytosol
• Process antigens through the proteasome
• Display antigenic peptides bound to class I MHC molecules for CD8+ T cell recognition
• Differentiated CD8⁺ cells kill infected host cells or tumor cells without dendritic cell assistance.
• Occurs when viruses infect cells other than dendritic cells or tumors arise from different cell types

Role of MHC-Associated Antigen Presentation

• Immuno-dominant peptides bind the MHC molecules in a specific way presented to T-cells
• Class I MHC pathway presents antigens to cytotoxic T lymphocytes
• Class II MHC pathway presents antigens to helper T cells

Functions of Antigen Presenting Cells

• Display peptides for recognition by T-cells
• Express additional signals (like B7-CD80, CD86 binding to CD28) for T-cell activation

Antigen Recognition by B-Cells and Other Lymphocytes (Follicular Dendritic Cells)

• Follicular dendritic cells (FDCs) are found in B-cell-rich lymphoid follicles (lymph nodes and spleen)
• They display intact native antigens bound by antibodies (or complement as C3b, C3d) to activate B cells, and induce affinity antibody maturation
• FDCs aren't derived from bone marrow
• Unlike other dendritic cells, FDCs don't process or present antigens to T cells