Lecture 2: Acquired Immunity
Movie of B and T cell Interaction
- Acquired Immunity
- Antigen Presentation
- Humoral Immunity
- B-Cells +B-cell receptor
- T-Cells + T-cell receptor
- MHC, class I and class II
- Lymphatic System
- Mucosal associated lymphatic tissue
- Clonal Selection
Top frames shown Ca2+ levels in T-cells, red means high Ca2+. Bottom frames show GFP labeled B Cell.
2. Molecules and Cells of the Acquired Immune System.
Humoral Immunity: soluble factors in the serum (e.g. antibodies)
Cellular Immunity: associated with cells
- Mature in the bone marrow (or bursa in birds)
- B-cell receptor binds foreign material (proteins, carbohydrates, etc.)
- receptor is a membrane bound antibody (IgM) plus two copies of a hetero-dimeric signaling domain (Iga
). Cytoplasmic section of Iga
can be phosphorylated, initiating a kinase signal cascade.
- All B-cell receptors are identical on a single B-cell, but diversity is on the order of 108 different B-cells.
- Stimulated B-cells differentiate into plasma cells that secrete copious quantities of antibody.
- Stimulated B-cells also form memory B-cells that do not secrete antibody.
- Stimulation of B-cells is enhanced by T-cells.
- Produced in bone marrow, but mature in the thymus.
- Recognize foreign peptides bound to major histocompatibility proteins (MHC) via the T-cell receptor.
- T- cell receptor composed of either a
chains or d
- Each T-cell has a homogenous population of T-cell receptor, but diversity is estimated to be on the order of 1012.
- Associated with phosphorylation signaling domain (CD3) (Cluster of Differentiation 3), composed of z
T-helper cells (TH):
- express CD4 (Cluster of Differentiation 4) on surface (CD4+)
- CD4 recognizes class II MHC (self) in complex with foreign peptides on antigen presenting cells, leading to activation of TH cell.
- Activation causes release of cytokines that activate B-cells, macrophages, Tc cells.
Cytotoxic T cells (TC)
- express CD8 on cell surface (CD8+).
- CD8 recognizes class I HMC/foreign peptides on almost any cell, leading to formation of a cytotoxic T lymphocyte (CTL)
2.3 MHC Complexes: Heterodimeric and membrane bound.
Class I - MHC
Class II - MHC
Type of cell
Antigen Presenting Cells (APC):
2.4 Development of Immune Cells:
3. Example of Humoral and Cellular Cooperation In Bacterial Infection (A day in the life of a B-cell)
- Progenitor B-cell develops into mature B cell in bone marrow, developing a unique antibody on its surface.
- If the antibody does not recognize self, then the mature B-cell is allowed to leave the bone marrow (107 new B-cells are produced/day).
- B-cells that encounter a foreign particle that can bind to the immunoglobulin on the cell surface become stimulated. If the B-cell does not have a successful encounter it dies within a few days.
- In addition to B-cells, macrophages and dendritic cells may also ingest foreign particle.
- Bound bacteria are internalized by endocytosis (B-cells), or phagocytosis.
- Bacterial peptides, complexed to class II MHC molecules, are presented on the surface of B-cells, macrophages, and dendritic cells.
- Specific TH-cells recognize foreign peptide bound to class II MHC, via CD4/T-cell receptor-MHC/peptide interactions, leading to activation of the TH-cell, cell division of that particular TH-cell, and subsequent formation of memory TH-cells.
- Activated TH-cells secretes cytokines that activate B-cells.
- Cytokines induce the differentiation & cell division of B-cells into antibody secreting plasma cells and memory B-cells.
- Plasma cells can secrete 103 molecules of antibody/sec! Fortunately, plasma cells live only a few days, but can produce about 1010 antibodies in that time.
- Antibody produced by plasma cells coats (opsinizes) bacteria, leading to more efficient phagocytosis of the foreign particles as well as cell destruction by complement.
- Subsequent infection by the same bacteria will lead to a more rapid response because of the presence of memory T- and B-cells. The primary response occurs within 14 days. The secondary response occurs within 3 or 4 days and produces 10-100 fold more antibody.
- Note that in four days a single E. coli will double about 200 times, giving rise to more bacterial cells than the number of cells in the human host. Clearly, innate responses play an important role.
- The activation of B- and T-cells by foreign antigen leads to an increase in the number of both types of cells. This antigen-dependent amplification of cells is referred to as clonal selection, since a specific sub-population, or clone, of B and T cells is involved.
3. Organs of the Immune System:
3.1 Primary organs:
- Thymus: Responsible for maturation of the T cells. Only T-cells that can recognize foreign peptides in complex with self MHC are allowed to leave the thymus.
- Bone Marrow: Responsible for maturation of B cells. Only B cells that express an intact immunoglobulin that recognizes foreign molecules are allowed to leave the bone marrow. B-cells that recognize self are destroyed.
3.2 Secondary organs:
- Traps foreign particles from the blood via dendritic cells. B-cells and T-cells activated by dendritic cells
- Traps local foreign bodies near the source of infections. Drains fluid from cells to lymph nodes and follicles, eventually returning fluid to the blood. Nodes and follicles contain B-cells, T-cells, macrophages, and dendritic cells. Dendritic cells engulf foreign particles, leading to activation of B and T cells.
- Highly organized follicles are present in small intestine (Peyerís patches) and tonsils and are part of the Mucosal-Associated Lymphoid Tissue (MALT)
Mucosal-Associated Lymphoid Tissue:
- Lymphoid follicles adjacent to mucosal membranes (e.g. tonsils, Peyerís patches).
- Specialized M-cell in wall of mucus membrane entraps foreign particle, delivering it to lymphocytes on the other side of the mucosa. This leads to activation of B-cells which migrate to the mucosa and deliver antibodies (IgA class) across the mucosal membrane.
3.3 Circulation Though the Lymphatic System.
- A lymphocyte in the blood will enter the lymphatic system 2-12 hours after it is released from the bone marrow or thymus.
- Approximately 3x1011 lymphatic cells flow through the system on a given day.
- A similar number are processed through the spleen.
- This high flux of cells insures that a foreign antigen will meet the appropriate B and T cells within a short period of time.