Adaptive Immunity - Cellular Response

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Adaptive Immunity - Cellular Response

T cells are lymphocytes that directly or indirectly eradicate pathogens. They respond to intracellular targets, as opposed to the B cells of the humoral arm, which respond to extracellular microbes.

T cell Life Cycle Origins: They arise from stem cells in the bone marrow. Maturation: T cells mature in the thymus (T is for Thymus): maturation involves positive and negative selection, and gives rise to naïve (non-activated) cells defined by the presence of either CD4 or CD8 proteins on their surfaces. Activation: In the secondary lymphoid organs, such as the lymph nodes and spleen, naïve T cells are activated by antigens; the naïve T cells become functional effector cells. Apoptosis: After the pathogen is eradicated, most of the effector cells undergo apoptosis; otherwise, they pose a potential danger to the host cells. Differentiation: Some of the T cells differentiate to become memory cells, which will respond if/when the host is exposed to the same antigen – thus, the secondary response to subsequent exposure can occur much faster.

MHC

Major Histocompatibility Complex (MHC) molecules present peptide antigens that activate T-cells.

Class I MHC molecules

Present fragments of antigens that are synthesized endogenously – i.e., peptides derived from viral antigens produced within the cells. Class I MHC molecules are only recognized by naïve CD8+ T cells and their Cytotoxic T cell descendants.

Class II MHC molecules

Present fragments from extracellular microbes and pathogens – i.e., peptides derived from extracellular microbes. Class II MHC molecules are only recognized by naïve CD4+ T cells and their Helper T cell descendants.

T Cell Maturation

Thymic education - two selective mechanisms that eliminate T cells that would otherwise harm the host: Positive selection ensures that the surviving T cells can recognize the MHC complex, which is necessary for their activation, while negative selection ensures that self-destructive T cells are eliminated.

Positive selection

Occurs in the thymic cortices

Immature T cells are exposed to cortical epithelial cells displaying self-MHC complexes: The T cells that recognize the MHC complexes survive Those that fail to recognize the MHC complexes undergo apoptosis.

Negative selection

Occurs in the thymic medullae

T cells are exposed to MHC complexes with self-antigen: Those T cells that do NOT respond to the self-antigen survive The T cells that DO respond undergo apoptosis.

T Cell Types:

Ultimately, thymic maturation produces three main types of T cells, which we designate based on their unique cell surface proteins: CD8+, CD4+, and CD4+/CD25+.

Regulatory T Cells CD4+/CD25+ T cells are Regulatory T cells; they can suppress the activity of the other T cell types via expression of Cytotoxic T Lymphocyte Antigen 4 (CTLA-4).

T-Cell Receptors::

In addition to the CD proteins, naïve T cells also express receptors (T-Cell Receptors, TCRs) for specific antigens; binding with their specific antigen induces their activation.

T Cell Activation

Activating Cells:

MHC class I molecules are displayed by all nucleated cells (in other words, most body cells except red blood cells).

MHC class II molecules are displayed by dendritic cells, macrophages, and B cells – because of this unique ability, these are referred to as "antigen-presenting cells."

However, be aware that B cells do not activate naïve T cells; they stimulate mature Helper T cells as part of their own activation (discussed in detail, elsewhere).

As we learned earlier, CD8+ and CD4+ T cells recognize different MHC classes; this means that they can only be activated by cells displaying the appropriate MHC molecules.

An Activation Example:

1. An antigen-presenting cell, such as a dendritic cell, recognizes and engulfs a microbe. 2. It digests the microbe and re-packages a peptide fragment with an MHC class II molecule on its surface. 3. The MHC- antigen complex is recognized by a naïve CD4+ cell, which is subsequently activated. Notice that if the antigen-presenting cell displayed only antigens complexed with MHC class I molecules, the CD4+ cell would not have recognized it.

Activating mechanisms in more detail:

CD8+ T cell:

2-signal activation of a CD8+ T cell, which differentiates to become a cytotoxic cell.

The cell surface of the CD8+ has the T-cell Receptor Complex (TCR complex), which consists of the following components:

The T-cell receptor, which is specific to the peptide antigen displayed by the MHC molecule; CD3 proteins; and, the CD8 protein, which recognizes and interacts with the MHC class I molecule of the nucleated cell.

The representative nucleated cell displays the class I MHC - antigen complex.

The interaction between the TCR complex and nucleated cell allows for the second signal, which involves co-stimulation between CD28 and B7-2.

Activation triggers proliferation, aka, cloning, of the T cell and differentiation into the effector type – which, for CD8+ cells, is the Cytotoxic T cell. These processes are guided by cytokines, which are released by T cells and antigen-presenting cells.

CD4+ T cell:

2-signal activation of a CD4+ T cell, which differentiates to become a Helper T cell.

The dendritic cell surface displays the MHC II-antigen complex.

The CD4+ cell has the TCR complex: the T-cell receptor, which is specific to the antigen; the CD3 molecules; and, the CD4 protein that interacts with the MHC II molecule on the antigen-presenting cell.

The second signal comprises co-stimulation: interaction between CD28 on the surface of the T cell and B7-2 on the dendritic cell.

Activation results in proliferation and differentiation to effector cells.

Effector Cell Functions

Cytotoxic T cells directly kill pathogen-bearing cells via the following steps: 1. The T cell recognizes the MHC I – antigen complex. 2. Docking brings the two cell membranes in close association. 3. The T cell releases perforins, which form a pore in the infected cell's membrane. 4. The cytotoxic cell releases granzymes, which move through the pore and trigger apoptosis of the infected cell.

Helper T cells, the products of activated CD4+ cells, have multiple roles in both innate and adaptive responses:

They amplify the innate response via cytokine release and recruitment of neutrophils and macrophages.
They activate B cells, which mediate the humoral arm of the adaptive immune response.
They activate cytotoxic T cells, in part by upregulating the expression of co-stimulatory molecules on dendritic cells.
Superantigens, such as Staphylococcus bacteria, are super potent activators of CD4+ cells.

4 subsets of Helper T cells:

Th1: develop under the influence of interferon-gamma and IL-12.

Anti-viral activity, macrophage activation, and induce cytotoxic T cell differentiation; when unregulated, they are associated with autoimmune diseases. This subset produces IL-2 and interferon-gamma.

Th2: develop under the influence of IL-4.

This subset is particularly important in defense against worms and in mobilization of eosinophils; they are associated with allergies and asthma. They produce IL-4, IL-5, and Il-13.

Th17: develop under influence of Tissue growth factor-beta, IL-6, IL-1, and IL-23.

This subset recruit neutrophils and monocytes. They are also associated with autoimmune disease. They produce IL-17 and IL-22.

Follicular helper T cells: differentiation is thought to require interaction with B cells.

Follicular helper T cells promote the humoral immune response and produce IL-21.

Adaptive Immunity - Cellular Response

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