Lymphocyte Activation Flashcards

T Cell vs. B Cell Antigen Recognition

  • T cells require antigens to be processed and presented via MHC molecules.
  • B cells can recognize antigens in their native form, including carbohydrates and lipids.
  • T cells will never see free-floating antigens, unlike B cells.

T Cell Expansion and Differentiation

  • T cell expansion and differentiation are critical steps in the adaptive immune response.

Cross Presentation

  • Cross presentation is a mechanism where antigens are presented on MHC class I molecules, even if they are of extracellular origin.
  • This allows for the activation of CD8+ T cells.

Four Major Steps of T Cell Activation

  • The four major steps of T cell activation involve the immunological synapse and co-stimulatory molecules.
  • The two-signal hypothesis is critical, where the first signal is antigen recognition and the second is co-stimulation.

Immunological Synapse

  • The immunological synapse is a close contact between the antigen-presenting cell (APC) and the T cell.
  • Adhesion molecules anchor the two cells together.
  • Mutations in adhesion molecules can lead to an inability to fight infections.
  • Some molecules within the synapse inhibit activation, thus regulating T cell activation.

Signal Transduction

  • Signal transduction follows the engagement of the T cell receptor (TCR).
  • The engagement of the antigen on the MHC seen by the T cell receptor gives signal number one.
  • Co-stimulatory molecules give signal number two.

B Cells

  • B cells can be activated in a T-dependent or T-independent manner.
  • Large carbohydrate molecules can trigger a B cell response without T cell help.

Origin and Function of Lymphocytes

  • B cells originate and mature in the bone marrow.
  • T cells originate in the bone marrow but mature in the thymus.
  • T cells mediate cell-mediated immunity.
  • B cells produce antibodies, providing humoral immunity.
  • Both cellular and humoral immunity depend on cells.
  • Innate immunity precedes adaptive immunity.
  • T cells require antigen presentation via MHC molecules.
  • B cells can act as APCs themselves.
  • APCs link innate and adaptive immune systems.

Kinetics of Immune Response

  • After initial exposure to an antigen, APCs present to T cells and activate naive B cells.
  • There is clonal expansion of B and T cells.
  • Cells differentiate into antibody-producing cells (B cells) and effector cells (T cells).
  • The response wanes after antigen elimination.
  • Memory T and B cells remain for future responses.

Morphology of Lymphocytes

  • Resting lymphocytes have a high nucleocytoplasmic ratio.
  • Activated B cells have larger cytoplasm with expanded endoplasmic reticulum.
  • Activated T cells (blasts) are larger than naive lymphocytes.
  • Plasma cells (differentiated B cells) have an eccentric nucleus.
  • T cells undergo significant morphological changes upon activation.

Dendritic Cells

  • Dendritic cells are strategically located to maximize encounters between antigens and T cells.
  • They perform phagocytosis (eating large elements) and pinocytosis (drinking smaller elements).
  • MHC class II molecules are associated with antigens engulfed through phagocytosis and pinocytosis.
  • CD4+ T cells are activated through this pathway.

Cross-Presentation Details

  • Cross-presentation allows extracellular pathogens to be loaded onto MHC class I molecules.
  • CD8+ T cells are activated via cross-presentation.

Dendritic Cell Migration

  • Dendritic cells move antigens to resident dendritic cells.
  • In peripheral tissues, dendritic cells have remarkable shapes.
  • They migrate to the lymphatic circulation and lymphoid tissues.

B Cells as APCs

  • B cells are also important antigen-presenting cells.
  • Dendritic cells have pattern recognition receptors (PRRs) that recognize pathogen-associated molecular patterns (PAMPs).
  • Activated dendritic cells migrate to T cell zones in lymph nodes.
  • They express MHC class I or class II, co-stimulatory molecules, and cytokines.

APC Journey

  • APCs bring antigens to the lymph node.
  • Antigens are recognized by T cells (CD4+ or CD8+).
  • Expansion and differentiation start in the lymph node.
  • Differentiated cells migrate into the circulation.
  • T helper cells provide help, and B cells enter peripheral tissues.
  • Phagocytes perform phagocytosis, and cytotoxic T lymphocytes (CTLs) kill infected cells.

Initial Steps of APC and T Cell Contact

  • Extracellular antigens are processed and expressed on class II molecules, activating CD4+ T cells.
  • Intracellular antigens are loaded on class I molecules, stimulating CD8+ T cells (MHC restriction).

Cross Presentation Definition and Mechanisms

  • Cross-presentation occurs when APCs phagocytose pathogens and present exogenous antigens to CD8+ T cells.
  • It allows presentation on class I molecules, crossing the dogma of MHC restriction.
  • Two pathways exist: cytosolic and vacuolar.
  • The cytosolic pathway involves TAP transfer to the endoplasmic reticulum and is affected by proteasome inhibitors.
  • The vacuolar pathway involves phagosomes and lysosomes and is sensitive to lysosomal inhibitors; it does not involve TAP.

Role of TAP

  • TAP (transporter associated with antigen presentation) is typical of class I presentation.
  • Dendritic cells can engulf infected cells and present viral antigens on class I molecules to amplify the response when CD4+ T cells are insufficient.

Dendritic Cells as Adjuvants

  • Dendritic cells react to dangerous signals.
  • They express MHC molecules, co-stimulatory molecules, adhesion molecules, and cytokines.
  • This creates the immunological synapse.

Immunological Synapse Details

  • The immunological synapse is a profound remodeling of cell membranes with reorganization of the cytoskeleton and mobilization of lipids.
  • It attaches cells together and regulates the reaction to prevent constant T cell activation.
  • There is cross-talk: APCs talk to T cells, and T cells talk to APCs.

Four Steps in Activation at the Immunological Synapse

  • Recognition: The T cell receptor recognizes the peptide loaded on a class I or class II molecule, providing specificity.
  • Co-receptors: CD4 for helper T cells and CD8 for cytotoxic T cells stabilize the interaction.
  • Adhesion molecules: LFA1 (integrin) binds ICAM1 (immunoglobulin superfamily), maintaining stability.
  • Co-stimulatory molecules: B71 (CD80) and B72 (CD86) bind to CD28, signaling the cell to become truly activated.

Inhibitory Receptors

  • Inhibitory receptors CTLA-4 and PD-1 terminate T cell activation and are targets for therapy.
  • They can reactivate anti-tumor T cell responses.

ICAM-1 and Immunoglobulin Superfamily

  • ICAM-1 belongs to the immunoglobulin superfamily (IgSF), which shares structural similarities with MHC molecules and CD28.

Costimulation Importance

  • Costimulation is crucial for T cell activation; without it, cells may become unresponsive or tolerant.
  • CD80 and CD86 (B7) binding to CD28 is required for a cascade of events that produce well-activated T cells.

Cytokines and Chemokines

  • Production of cytokines and chemokines occurs.

Summary of Immunological Synapse Events

  • Specificity is provided by the antigen loaded on the MHC molecule (signal 1).
  • Signal 2 is provided by co-stimulatory molecules engaging CD28 on the T cell side and required for cell survival.
  • Production of cytokines like interleukin-6, interleukin-12, TGF beta, and IL-4 continues the differentiation process.

Signal Transduction and Transcription Factors

  • Association between the T cell receptor and the CD3 molecule occurs, involving ITAM motifs.
  • Activation of transcription factors such as NF kappa B, AP1, and NFAT occurs.
  • These transcription factors translocate to the nucleus to modify gene transcription.
  • Interleukin-2 (IL-2) is produced, playing a role in proliferation and differentiation of T cells into effector cells.

B Cell Antigen Recognition

  • B cells have immunoglobulin molecules on their surface with variable regions for antigen binding and a hinge region for flexibility.
  • The B cell receptor consists of the immunoglobulin plus an associated transmembrane molecule (CD79).

B Cell Development

  • B cells develop from stem cells through various stages (pre-B cells, pro-B cells) and express immunoglobulins on their surface.
  • They perform antigen presentation and antibody production within germinal centers.
  • Some differentiate into memory B cells, while others become plasma cells.

B Cell Response Kinetics

  • B cells increase in numbers and differentiate into plasma cells.
  • The secondary antibody response is more potent with higher antibody levels and improved affinity.

T-Dependent Antibody Response

  • T cells are stimulated by APCs, and contact occurs between T cells and B cells in the T cell zone.
  • Activation produces short-lived plasma cells, followed by movement to the germinal center for further differentiation into germinal center B cells, memory B cells, and plasma cells.

T-Dependent vs. T-Independent Antibody Production

  • Protein antigens trigger a T-dependent response.
  • Follicular B cells expressing IgM pick up protein antigens and, with T cell help, undergo class switching (IgG, IgA, IgE).
  • Carbohydrate antigens trigger a T-independent response by bridging many surface IgM molecules on B1 cells and marginal zone B cells.
  • T-independent responses produce mainly IgM without much isotype switching.
  • Toll-like receptor ligands and complement components also play a role.