NF-AT Pathway and T Cell Activation

NF-AT Pathway

• IP3 facilitates intracellular calcium release from storage.
• Calcium binds to calmodulin, activating calcineurin.
• Dephosphorylation of NFAT occurs, allowing it to enter the nucleus for gene transcription, e.g., IL-2 production.
• Inhibiting this pathway can reduce NFAT activation by preventing dephosphorylation.
• Similar signaling pathways exist in B cells, maintaining activation via PLCgamma2.

Secondary Signals in T Cell Activation

• CD4 and CD8 T cells require secondary signals for activation.
• CD28 binds to B7 on antigen-presenting cells (APCs) for full T cell activation.
• If T cells recognize antigen without co-stimulation, they may enter a state of anergy.
• CD28 modulates signaling pathways including NFAT, NF-kB, and AP-1.

CTLA-4 and T Cell Regulation

• CTLA-4 is homologous to CD28 but has a stronger affinity for B7.
• CTLA-4-Ig is a drug that blocks B7, inhibiting T cell activation.
• CTLA-4 is crucial for maintaining T cell homeostasis.

T Cell and APC Interactions

• Costimulatory signals and adhesion responses facilitate T cell interactions.
• LFA-1 binding to ICAM-1 enhances stability of T cell-APC contact.
• Initial binding between TCR and APC increases affinity of LFA-1/ICAM-1 interaction.

B Cell Development and Antibody Generation

• BCR/Ig functions in diverse immune roles, establishing central and peripheral tolerance.
• Adaptive immunity hallmarks: clonality, specificity, diversity, and repertoire.
• TCR is monovalent while BCR is bivalent, aiding in immune response diversity.
• Thymic selection processes ensure T cells interact appropriately with MHC molecules.

MHC and Transplantation

• Graft rejection mechanisms: direct (TCR recognizes foreign MHC) and indirect (APCs present foreign MHC on recipient's MHC).
• HLA typing ensures compatibility during transplantation with vast combinations of MHC molecules.

Immune Evasion Mechanisms

• Pathogens can evade immune detection by inhibiting the loading or expression of MHC molecules.

Innate Immunity Overview

• Innate immune response is rapid (minutes/hours) and recognizes patterns associated with pathogens.
• Characteristic features include germ line-encoded receptors and strong self/nonself discrimination.
• Complement proteins and interferons are key components of innate immunity.

Pathogen Recognition

• PAMPs (Pathogen-Associated Molecular Patterns) are recognized by PRRs (Pattern Recognition Receptors) throughout the immune system.
• Major cells with PRRs include neutrophils, dendritic cells, and macrophages.

Cellular Responses of Innate Immunity

• Macrophages and dendritic cells arise from monocytes and infiltrate tissues.
• Neutrophils are present in blood but migrate to tissues during infections; they have a short lifespan.

Macrophage Functionality

• Phagocytosis involves engulfing pathogens and destroying them with lysosomal enzymes.
• Respiratory burst increases oxygen use, generating toxic forms of oxygen to kill pathogens.
• Cytokines produced by macrophages include IL-1, IL-6, IL-8, IL-12, and TNF-α.

Complement System

• Classical pathway is triggered by antibody-antigen complexes; the alternative pathway responds to microbial cell walls.
• Both pathways convert C3 into C3b and C5b, which facilitate opsonization and membrane pore formation leading to pathogen lysis.

Toll-Like Receptors (TLRs)

• TLRs detect specific microbial components, triggering immune responses tailored to the pathogen type.
• Engagement of TLRs activates various transcription factors that modulate cytokine production, enhancing immune responses against pathogens.

Adaptive Immunity Basics

• Adaptive immune response is characterized by clonal selection and the differentiation of CD4 cells according to infection type.
• B cells undergo maturation in the bone marrow, while T cells develop in the thymus, essential for effective immune responses.