Chapter 4 - Adaptive Immunity

Characteristics of Adaptive Immunity

specificity

memory of prior exposure

enhanced response upon repeated exposure

takes longer to become activated, but is longer lasting than innate defenses

gene rearrangement

clonal expansion

2 branches of adaptive immunity

1. Cell-mediated

   1. T cells

      1. Tc = kill target cells infected with intracellular pathogens and cancer cells

      2. Th = don’t directly kill, but control immune response through release of cytokines

2. Humoral Immunity

   1. B cells and antibodies

      1. labeling targets for ingestion

      2. aid in rendering viruses and toxins innert through neutralization

      3. block adhesion of microbes

Clonal expansion

causes delay between initial infection and effective adaptive response

effector cells

proliferation of B cells into plasma vs memory cells

Gene rearrangement responsible for…

responsible for different interaction with different epitopes

Effector cells

Th, Tc, B, & plasma cells

Memory cells

after clonal expansion

long lived, will become reactivated for specific microbe

reactivate rapidly with a stronger response

Lymphocyte Differentiation

begins very early in fetal development - in the liver

bone marrow then becomes source of lymphocytes and remains the primary producer of HSC at birth and throughout adult life

T cell differentiation

1. immature T cells transported from BM to thymus

   1. thymus is divided into outer cortex an inner medulla

2. one in thymus, precursor cells become known as thymocytes

3. thymocytes begin to migrate toward the cortex under the direction of chemokines

   1. chemokines = cytokine that control movement of cells

4. takes 3 weeks for thymocyte to travel from cortex to medulla during the maturation process

5. 3 major stages of differentiation

   1. double negative

   2. double positive

   3. single positive

   4. mature T cell

T-cell differentiation stage 1

Double-Negative (DN) Stage 1

• chemokines drive migration of T-cell precursors to the cortex of the thymus

• thymocytes at this stage lack both CD4 and CD8 surface markers

  • “fate” not decided (Tc vs Th)

• thymocytes undergo rearrangement of genes coding for the beta chain of the TCR

• gene segments are selected and joined together to produce a unique-antigen binding site

  • gene rearrangement halts after a functional beta and alpha chain have been produced

Figure 4-2 (label)

T-cell differentiation stage 2

Double-Positive (DP) Stage 2

• After beta chain on cell surface of T cell

• Thymocytes express CD4 and CD8

• positive selection occurs:

  • thymocytes survive if their TCR moderately recognizes MHC antigens on stromal cells in the cortex

    • “fate” is decided

      • thymocyte binds to MHC I…CD8+ stays on cell

      • thymocyte binds to MHC II…CD4+ stays on cell

• negative selection occurs:

  • strong binding leads to apoptosis because cells recognize self

  • no binding leads to apoptosis because cells are nonfunctional

T-cell differentiation stage 3

Singe-Positive (SP) Stage 3

• Cells are + for only CD4 or CD8

• Negative selection:

  • thymocytes that bind to self-antigens on thymic stromal cells undergo apoptosis

  • takes place in corticomedullary region and medulla

• survivors = mature T cell

T-Cell Differentiation: Mature T Cells

survivors of positive and negative selection exit thymus and recirculate between the blood and lymphatics

• naive until come in contact with antigen

CD4 T cells are T helper and T regulatory cells = secrete cytokines and influence Ab production

CD8 T cells are cytotoxic T cells = they kill target cells

B Cell Differentiation location and involvement

occurs in BM

starts with HSC that develops into early lymphocyte progenitor

involves

• development of mature immunocompetent B cells

• activation of B cells by Ag

• Differentiation of B cells into Ab-producing plasma cells

B-Cell Differentiation

Ag-Independent

Cells involved

Ag-Independent

• Pro-B cells

• Pre-B cells

• Immature B cells

• Mature B cells

Fig 4-7

B-Cell Differentiation: Pro-B Cells

• rearrangement of genes that code for heavy and light chains of Ab molecules occur

• this creates a variable region with specificity for a particular Ag in each cell

• the cells must successfully rearrange one set of heavy-chain genes to become pre-B cells

B-Cell Differentiation: Pre-B Cell

• heavy Mu chains of IgM class accumulate in cytoplasm

  • combine with short Ig-a and Ig-b chains to form a pre-B cell receptor on the B-cell surface

B-Cell Differentiation: Immature B Cells

• Pre-BCR is replaced with a functional BCR containing two light chains (gone through gene rearrangement) and two heavy chains of the IgM class

• BCR has a variable region that determines specificity for the Ag and serves as an Ag receptor

• B cells that have receptors for self-antigens are deleted in the bone marrow (apoptosis)

  • central tolerance

  • 90% of differentiated B-cells die because they bind to self-Ag

• Surface proteins include

  • CD21, CD40, MHC II

Immature B cells surface protein markers and functions

CD21

• receptor for C3d and enhances likelihood of contact between B-cells and Ag

CD40 & MHC II

• important for interaction of B cells with Th cells

B-Cell Differentiation: Mature B Cells

• Immature B cells that do not react with self-Ags and display the appropriate surface markers migrate to the spleen for further development:

• marginal-zone B cells

  • remain in spleen

  • respond quickly to BBP

  • differentiate into plasma cells after contact with Ag

• follicular B cells

  • migrate to lymph nodes and other secondary organs

  • recirculate

  • make contact with Th cells

  • differentiate into memory cells

• exhibit cell surface IgM and IgD

• surface immunoglobulisn provide activating signal to B cells when contact with Ag occurs

• when stimulated, enter the antigen-dependent phase, forming:

  • memory cells (follicular)

  • Ab-secreting plasma cells (marginal)

Majority of B cells are destined to be follicular or marginal B cells?

follicular B cells

In addition to IgM, what Ig do mature B cells also express

IgD

B-Cell Differentiation: Plasma Cells

• found in bone marrow and peripheral lymphoid organs

• produce antibodies

• abundant cytoplasmic Ig, but little or no surface Ig

• CD138 on cell surface for identification

Roles of T cells in adaptive immune response

• APCs activated during innate response

• T cells interact with APCs to initiate adaptive immune response

• T cells circulate throughout the bloodstream, lymph nodes, and secondary lymphoid tissue, looking for APCs displaying specific Ag fragments complexed with MHC

  • cell-to-cell, must be touching each other

• Cytokines drive differentiation of T cells into subsets

Th and Treg cell subsets/function

Th1

• produce IFN-g, IL-2, TNF-B

• activate Tc and macrophages to fight intracellular pathogens in cell-mediated immunity (intracellular infections)

Th2

• produce interleukins 4, 5, 6, 9, 13

• help B cells produce antibodies

• promote clearance of extracellular parasites and have a role in allergy

Th17

• produce IL-17 and IL-22

• recruit granulocytes in response to fight bacterial infections

• may be associated with pathology in some diseases

  • granulocyte activity can cause immune-mediated damage to cell

Treg

• CD4 and CD25

• suppress immune response to self-Ag and harmless Ag

• secrete inhibitory cytokines to inhibit proliferation of other T-cell populations

• 5% of our T cells

Tfh

• stay in lymph nodes

• interact with B and plasma cells

Action of cytotoxic T cells (Tc cells)

• CD8+

• bind to and destroy cells infected with intracellular parasites and viruses

  • release cytotoxic granules containing perforin and granzymes

  • ligation of death receptors

perforins

granzymes

ligation of death receptor

proteins that enter a target cell membrane to form a pore

serine proteases that can initiate the fragmentation of DNA in target cells

TCR recognizes Ag-complex with MHC which leads to expression of death-inducing protein (fas-ligand, fasL binds fas on target cell membrane which starts an apoptosis pathway in target cell)

Role of B cells in adaptive immune response

T-dependent antigens

response to T-dependent antigens

• require help of Th(2)(fh)

  • Ag is always a protein

• can switch from production of IgM to another Ab class (IgG)

• affinity of BCR increases during the immune response

• memory cells are generated (from follicular B cells)

Role of B cells in adaptive immune response

T-independent antigens

response to T-independent antigens

• do not involve Th

• polysaccharides with many repeating units cross-link BCRs

• Only IgM is produced

• memory not generated

• *usually marginal B cells