Lec 10 micro

How do we get the antigens to the T cells and B cells?

Dendritic cells take up bacterial antigens in the skin and then move to enter a draining lymphatic vessel. The dendritic cells bearing antigen enter the draining lymph node, where they settle in the T cell areas. Then there’s an activation of adaptive immune response through macrophages.

Where are B cells and T cells located?

B cells are mainly in the B cell follicles and T are mainly in T cell area. They are separated into different regions, but they come together when an immune response is needed. when B cell finds its antigen, it has to move toward the T cell area to find the correct helper T cell

What is CD4 T cell (helper T cell) activation like?

Most are naive T cells once they come in contact with antigen presenting cells and antigen with MHC ll, naive CD4 T cells can become activated by TCR signaling. Then there’s an autocrine stimulation with IL-2 which causes antigen-specific CD4 T cells to proliferate. TCR signaling increases IL-2 sensitivity by upregulating the alpha subunit, thereby creating a high affinity IL-2

Activation of B cells

• Naive B cells in the lymph node recognize antigen brought in by lymphatic duct.

• Antigen-BCR complexes are internalized by receptor mediated endocytosis (BCR grabs onto an antigen and then the B cell pulls the antigen inside the cell)

• Antigens are processed and presented on MHC ll

• MHC II-peptide complex interacts with specific TCR on Tfh cell (Tfh cell recognizes a peptide derived from the B cells antigen)

• Tfh cell provides cytokines and CD40 stimulation to activate the B cell

Tfh (T follicular helper cells)

important for B cell response, these interact with B cells and provide cytokines and CD40 stimulation

CD40

protein present on B cell surface, the Tfh cell has a matching protein called CD40L which when they bind together allows CD40 stimulation which tells the B cell to keep going.

Regulatory T cells

repress the adaptive immune responses (control or limit this response)

Once CD4 T cells are activated what do they differentiate into?

Th1, Th2, TfH, TH17and regulatory cells

TH17 CD4 T cells

enhance neutrophil response

TH2 T cells

activate cellular and antibody response to parasites

TFH cells

activate B cells maturation of antibody response

Treg

suppress other effector T cells

Where do naive B cells enter and exit through the spleen?

Go in through the blood vessels as naive B cells and come out through the efferent lymphatic vessel as a active B cells

what is the process of antigen/B cell/ and T cells during activation?

Antigen is brought to the lymph node by dendritic cells, and afferent lymph brings soluble antigen which washes over the cells of the lymph node. Naive B cells enter the LN through the bloodstream and cross into the T cell area of cortex through the HEV (high endothelial venule). If the BCR is specific to antigen present, the B cell will process the antigen and present it on MHC II. The cell now needs to find a cognate T cell or it will die. The B cell now moves through the T cell region looking for a cognate CD4 T cell (specific to same antigen). Once the correct cell has been found the cells stimulate each other to proliferate. The T cell clones are now Tfh cells.

What is primary focus?

The B cells produce small quantities of IgM. Some of these B cells differentiate into IgM-producing plasma cells. These short-lived plasma cells migrate to the medullary chords where they accumulate and produce soluble IgM. IgM drains with the lymph and enters the blood stream.

What happens to the B cells that do not stay in the primary focus?

they migrate to the B cell region of the cortex together with their cognate Tfh cells. these B cells continue to proliferate to form the germinal center.

What happens in the germinal center?

Individual B cell clones undergo repeated somatic hypermutation and selection which drives affinity maturation of the BCR. The affinity maturation process takes several days.

What happens during affinity maturation of the B cell receptor in the germinal center?

B cells divide and go into somatic hypermutation (mutant variable region of Ig genes) is a good mutation and makes BCR, then gets tested against the antigen if it binds then they redo the process if it doesn’t then the cell undergoes apoptosis.

What other actions are taking place while affinity maturation is proceeding in the germinal center?

Low affinity IgM is being produced by medullary plasma cells. Short lived plasma cells start dying off and blood IGM levels peak. As affinity maturation is optimized, B cells class switch from making IgM to IgG. Most of these cells then differentiate into IgG-producing plasma cells.

What is IgM?

long lived plasma cells that leave the lymph node and migrate to the bone marrow where they produce large quantities of IgG which is released into the bloodstream. This helps clear the infection and antigen disappears from the lymph node.

what is distributed amongst secondary lymphoid tissues?

class switched B cells differentiate into memory B cells which migrate throughout the body distributing amongst the…

What are the steps of a typical humoral response?

1. B cells enter the lymph node seeking antigen and cognate Tfh cells.

2. Antigen selected B cells proliferate

3. Some of the B cell clones differentiate into short lived plasma cells and migrate to the medulla of the node.

4. Medullary plasma cells secrete IgM which is released to blood and lymph

5. Some clones generated in 2 migrate to B cell area together with cognate T cells to form the germinal center

6. Individual B cell clones undergo somatic hypermutation in the variable regions of the Ig gene. This introduces small point mutations in an effort to improve binding affinity of the Ig molecule to the antigen in a step called affinity maturation. These receptors are tested by Tfh cells, and it improved will be stimulated to divide and hypermutate again. If not stimulated, cells will die by apoptosis. With several iterations of hypermutation and selection the Ig gene undergoes Isotype switching to make IgG.

7. Isotype-switched B cells differentiate into long lived plasma cells or memory B cells.

8. Long lived plasma cells migrate to bone marrow and secrete IgG

After activation B cells can take two major paths which are:

Path 1: Primary plasma cell pathway- B cells become plasma cells which then become IgM (early response/low affinity)

Path 2: Germinal center pathway- B cells enter the germinal center they start somatic hypermutation leading to isotype switching so now there is present IgG plasma cells or memory B cells. (fast response/high affinity)

What are memory B cells and the establishment of immunological memory?

These are produced by B cell proliferation but do not secrete antibodies. They have BCRs complementary to the antigenic determinant that triggered their production. They are long lived cells that stay in the lymphoid tissue, and they initiate antibody production if antigen is encountered again.

Primary response

happens on individual’s first exposure to the pathogen,the body has to find the correct lymphocyte, activate it, multiply and produce effector cells (takes a longer time)

Secondary (memory humoral responses)

happens during a later exposure to the same pathogen, the rapid IgM and IgG is due to reactivtation of memory B cells. This is the basis of immunity and is the reason we vaccinate

What is t independent antigens?

polysaccharides, A and B antigens associated with ABO blood types, bacterial capsules

What do T independent antigens do?

can directly stimulate B cells to produce antibody without the requirement of T cell help. These antigens are characterized by the same antigenic determinant repeated many times. They provide a strong activating signal to specific B cells. Theres no MHC involvement (non-peptide antigens), mostly IgM is produced

How are B cells transported to IgA?

due to Treg cells and TGF-b, secretory IgA is transported across epithelial layer by polymeric immunoglobulin receptor

Adaptive Immune Response against Viruses

virus infects cell, viral proteins synthesized in cytoplasm, peptide fragments of viral proteins bound by MHC I in ER, Bound peptides transported by MHC I to the cell surface, cytotoxic T cells recognize complex of viral peptide with MHC I and kills infected cell

(B cells make neutralizing Abs)

Activation of CD8 cells

Naive CD8 T cells are primed by activation of the TCR via MHC I. The cells reuqire co-stimulation, eithr through co-stimulatory molecules on dendritic cells or by IL-2 released by CD4 cells. Like CD4 cells, CD8 cells will upregulate the alpha subunit of the IL-2 receptor and undergo autocrine stimulation to proliferate and differentiate into cytotoxic T lymphocytes (CTL). Once activated CTL migrate into the lymph and bloodstream and home to inflamed tissues where they will kill any virus infected cells displaying the cognate antigen on MHC I.

CTLs kill using 2 primary mechanisms

1. Perforin-Granzyme Cytotoxic pathway: Perforin is released by CD8 makes pores, granzymes enter and activate apoptosis

2. CD95 cytotoxic pathway: CD8 makes CD95 ligand and binds to CD95 on the target cell, the death signal is transmitted into the target cell, then apoptosis happens

Cytotoxic lymphocytes (serial killers)

CTL recognizes and binds to virus infected cell, CTL programs target for death, inducing DNA fragments, CTL migrates to new target, the target cell dies by apoptosis.

Memory T cells

A subset of activated T cell clones becomes memory T cells; this happens for all CD4 and CD8 populations. These become re-activated more efficiently since they already have an activated phenotype and will proliferate, and resume effector function, upon presentation of antigen on appropriate MHC molecule