The cells of the adaptive immune response - T cell help and cellular immunity

What is lymphocyte trafficking?

• B cells enter into circulation from Bone Marrow, with a pre-determined antigenic specificity

• They are in tissue until they come to lymphoid tissue, where there are adhesion molecules, and it will squeeze between the endothelial cells

• When they leave the lymph nodes, specific receptors direct them to the region/target tissue, where the antibodies are needed

What is a germinal center?

• Process of clonal selection, made of cells which help B-cells grow after encountering antigen

  • Key Cells: follicular dendritic cells, holding antigens

  • Can interact with the antigen, which causes B cells to expand

  • Need help of cytokines from the Helper T Cells

• Located in secondary lymphoid follicle

What is the lifecycle of a B cell?

• Exits bone marrow, only B cells entering lymphoid tissue will survive

  • Most B cells die after exiting the bone marrow (2-3 days)

• If they enter lymphoid tissue and never encounter an antigen, they only live a few weeks

• If they encounter their antigen, they form germinal centers and plasma cells, are long-lived for years

How does clonal deletion work in B-cells?

Clonal Deletion in B Cells (Bone Marrow)

B cells are also produced in the bone marrow and undergo selection to ensure they do not produce antibodies that target the body's own tissues. The process for clonal deletion in B cells is a bit different from T cells, but it serves the same purpose: to prevent self-reactivity.

• Development and Testing in the Bone Marrow:
  As B cells mature in the bone marrow, they produce B cell receptors (BCRs), which are antibodies bound to their cell surface. These receptors are tested for self-reactivity by encountering self-antigens that are expressed in the bone marrow.

• Clonal Deletion (Negative Selection):
  If a developing B cell's BCR binds strongly to a self-antigen (meaning it recognizes the body’s own molecules as foreign), this B cell is deleted through a process called clonal deletion. Essentially, the body eliminates B cells that could generate antibodies against self-antigens, thereby preventing autoimmune diseases.

  In addition to clonal deletion, B cells that bind self-antigens weakly may undergo a process called receptor editing, where the B cell changes its receptor to avoid recognizing the self-antigen.

What is affinity maturation?

a process in the immune system where antibodies gain the ability to bind to antigens more effectively

• B cells undergo somatic hypermutation (SHM) of their immunoglobulin genes, which creates antibodies with increased affinity for antigens. These antibodies are then selected based on their affinity.

• Takes place in the secondary lymphoid tissues

Provide a summary of the B-Cell lifecycle.

1.) B Cells mature in the bone marrow, they enter circulation as virgin B cells with defined antigenic specificity (IgM and IgD)

2.) Enter lymphoid tissue where they undergo, class switching and affinity maturation

3.) Can produce IgM - producing plasma cells, low affinity, high avidity, low titer

4.) Can produce IgG - producing plasma cells, low affinity, high titer

5.) Can produce IgG - producing plasma cells, high affinity, high titer

• Higher affinity than the first

Where do T-cells come from?

• Mature in the thymus

What happens to the thymus as we age?

• Grows most between birth and puberty, then begins to atrophy

• T-cell output is most active before puberty, after which the size and activity are dramatically reduced, it is replaced with fat

• Explains why older individuals become more immuno-deficient and may need more vaccinations

What happens if there was no thymus?

• Defective antibody formation

• No hypersensitivity reactions

• No killing of virus or malignant cells

• No graft rejections, they cannot see it as being foreign

What is the process of clonal deletion in T-cells?

Clonal Deletion in T Cells (Thymus)

T cells are produced in the bone marrow but mature in the thymus. In the thymus, they undergo a selection process to ensure they can recognize foreign antigens (via the major histocompatibility complex, or MHC) but not react to self-antigens (the body's own proteins).

• Positive selection makes sure that T cells can recognize MHC molecules and are therefore capable of responding to foreign antigens.

• Negative selection eliminates T cells that could potentially recognize and attack the body's own cells (self-antigens).

• In essence, clonal deletion of T cells removes any T cells that might react to the body’s own tissues, thereby preventing autoimmunity.

What is the structure of a T-cell?

• Symmetrical, made up of a and B chains

  • Another form called yS (Gamma, Delta)

• T-Cells recognize short peptides

What are the two main types of T-cells?

1.) Helper T-Cells

• Drive expansion of B-Cells

• Has protein called CD4 bound to the surface, stabilizes interaction with antigen-presenting cell

2.) Cytotoxic T-Cells

• Kill viruses and malignant cells

What is MHCI?

MHC class I proteins are found on the surface of all nucleated cells and platelets, and are responsible for presenting peptides to other immune cells

• Helps cells know “self”

What is MHCII?

Only present on cells of the immune system

What type of T-cell is most common in ruminants?

• yS (Gamma-Delta) T-cells

• Most are localized at mucosal surfaces and skin, suggesting they may contribute to innate immunity, part of the first line of cellular defense against invading pathogens

• Livestock are up and running very quickly, need a good immune system right away

How might a B-cell undergo anergy?

If B-cells react to a self-antigen, they might undergo clonal deletion (if the self-reactivity is strong enough) or receptor editing (where the BCR is modified to avoid recognizing the self-antigen), however, if the self-reactivity is not strong enough to trigger clonal deletion or receptor editing, then anergy may occur

• Anergy is a form of functional unresponsiveness to self-antigens.

• It occurs when a self-reactive B cell binds to a self-antigen without receiving a secondary signal from helper T cells.

• The B cell becomes silenced and cannot mount an immune response, preventing autoimmunity.

• Central Tolerance: becoming anergic in BM

• Peripheral Tolerance: becoming anergic in circulation