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ImmunologyChapter7notes.docx

The Immune System Fourth Edition 2015

Immunology Chapter 7 notes: The Development of T Lymphocytes

1. Figure 8.14 from Janeway’s Immunobiology, 8ed. gives a good overview of the lifespan of a T cell. I am placing this figure on the PPT I post for a reference. You can refer to this figure throughout chapter 7 and 8 of your book as an extra source.

Where do T cells develop?

· T cell development happens in two primary lymphoid organs.

· Begins in the bone marrow and finishes in the thymus.

· Fig. 7.1

· In the bone marrow, a hematopoietic stem cell (HSC) differentiates into a multipotent progenitor cell (MPP), which then differentiates into a common lymphocyte progenitor (CLP), The CLP enters the blood and in the case of T cell production travels to the thymus.

· In the thymus, the CLP becomes a thymocyte. While still in the thymus,the thymocyte undergoes a maturation process. Part of this process tests the thymocyte’s ability to recognize self-MHC molecules.

· After a mature a T cell is formed, it leaves the thymus via the blood and enters a secondary lymphoid organ. It leaves the secondary lymphoid organ via the lymph and enters back into the bloodstream. An inactivated T cell will continue circulating through blood, secondary lymphoid organs and lymph until it recognizes antigen. You will see what happens when a T cell recognizes antigen in chapter 8.

· The mature T cell does not ever reenter the Thymus. In fact the thymus begins to degenerate one year after birth. This process is called thymus involution.

· Fig. 7.4

· Thymus involution

· The human thymus is developed before birth, but begins to degenerate approximately 1 year after birth. From 1 year old throughout a person’s lifetime the thymocytes within the thymus are being replaced with fat.

· What does this mean about T cells function throughout a persons lifetime?

· Even though fewer T cells get produced throughout a persons lifetime, there T cell function does not tend to decline. Unlike B cells, T cells are not short lived cells. They are long-lived cells that have the ability to self renew even in the absence of a thymus.

How do T cells mature in the thymus?

· Fig. 7.3

· A thymocyte travels through different sections of the thymus (cortex medulla) during different stages of maturation.

· Cortex is composed of cortical epithelial cells, immature thymocytes, macrophages

· Medulla is composed of medullary epithelial cells, mature thymocytes, dendritic cells and macrophages

Stages of Maturation:

1. Thymocyte to committed T cell

· A progenitor lymphoid cell enters the thymal cortex through the bloodstream. This cell expresses CD34 and CD44 (stem cell markers) (Figs. 7.7 and 7.5).

· The progenitor cell is influenced by two major molecular interactions with thymic stromal cells (epithelial cells). One interaction is with IL-7 signaling and the other with Notch 1 signaling. These interactions set off cell-signaling pathways that result in the transcription of genes needed during T cell development.

· IL-7 (interleukin – 7) is secreted by thymic stromal cells and binds to the IL-7 receptor on the progenitor cells.

· Fig. 7.6 Notch 1 is a surface receptor on thymocytes that interacts with its ligand on stromal epithelial cells.

· With these signals, the progenitor cells begin to divide and differentiate. During this process the expression of CD34 and CD44 is down regulated and the expression of T cell adhesion molecules such as CD2 and CD5 is upregulated. These cells are now considered double negative thymocytes because they do not exhibit (are negative for) CD4 or CD8 receptors.

· These cells are also considered committed to the T cell lineage at this point. However they still have not committed to becoming a particular type of T cell. The type of T cell they become is directed with the next events that occur in the thymal cortex.

· These double negative thymocytes now can further interact with stromal epithelial cells to divide and differentiate into either a γ:δ T cell or an uncommitted double positive thymocyte. (Fig. 7.7)

· These results are a product of gene rearrangement. (Fig. 8.22)

· Similar to B cell receptor development a Somatic recombination of V, D, and J genes is necessary to determine the T cell receptor (TCR) of each double negative thymocyte.

· During this process, double negative thymocytes begin to rearrange their γ, δ and β genes at the same time.

· If the γ and δ genes rearrange first the cell expresses a complete γ:δ TCR (TCR). This receptor will receive a signal that turns off the rearrangement of the β gene.

· The incidence of γ:δ TCR (TCR) formation before pre TCR (β gene rearrangement) T formation does not happen at a high frequency.

· When double negative thymocytes are rearranging their γ, δ and β genes the β gene usually rearranges first. It is then associated with a pre α gene and expressed as a pre TCR on the cell surface. When this happens, the pre TCR receives a signal that turns off γ:δ gene rearrangement and commits the cell to the α:β T cell lineage. *However it can still revert back to the γ:δ lineage during the next process (Fig. 7.7).

· (Fig. 7.13) For α gene expression an additional round of gene rearrangement occurs after the initial rearrangement event of the γ, δ and β genes. During this rearrangement event, the α gene is usually rearranged. However sometimes the γ and δ genes get rearranged instead and you get γ:δ T cells produced (Fig. 7.7).

· Most of the time the rearrangement event results in α gene expression. In this case the δ gene locus is deleted from the chromosomal DNA because it is encoded between the V and J genes of the α gene locus.

· This deletion solidifies the T cell in becoming an α:β T cell.

· γ:δ T cells produced at this point will leave the thymus and migrate to the epithelial tissues where they can serve multiple effector functions. There they live the rest of its life as a γ:δ T cell.

· If a committed α:β double positive T cell is produced during this process it will undergo further processing.

· A committed α:β double positive T cell at this point is still double positive and will undergo even more processing to differentiate into a particular type of α:β T cell (for example a CD8 + T cell). (Fig. 7.7)

· This processing is referred to as T cell positive and negative selection.

2. T cell Positive and Negative Selection

· Double positive T cell (a committed α:β T cell that expresses both CD8 and CD4 on its surface) Single positive T cell (a committed α:β T cell that expresses both CD8 and CD4 on its surface)

· Positive and negative selection of T cells occurs in two rounds. The first round happens in the thymal cortex and the second round happens in the medulla.

· Refer to video posted in slides for a summation.

· The first round – Positive selection (Fig. 7.16)

· Purpose: Determine if a thymocyte will be CD4 + or CD8+

· T cells are presented with antigen bound in MHC molecules. Cortical thymal epithelial cells and macrophages within the thymal cortex are the cells that present antigen.

· T cells with a TCR that recognize and bind MHC class I well receive a survival signal and differentiate to no longer express CD4. (Fig. 7.17)

· T cells with a TCR that recognize and bind MHC class II well receive a survival signal and differentiate to no longer express CD8. (Fig. 7.17)

· T cells that do not recognize and bind either MHC I or MHC II well receive a death signal and undergo apoptosis. Cortical macrophages clean up the dead cells.

· The second round – Negative selection (Fig. 7.18)

· Purpose: test T cells reactivity to self-antigen.

· T cells are presented with self-antigen bound in MHC molecules on the surface of medullary dendritic cells and macrophages within the medulla.

· These cells are able to express a wide range of self-antigen due to their phagocytic ability and a transcription factor called autoimmune regulator (AIRE).

· The transcription factor AIRE is produced by the medullary epithelial cells and causes the transcription and subsequent translation of hundred of tissue specific genes that the macrophages and dendritic cells may not have encountered otherwise. The production of these tissue specific genes in the thymus increases the amount of self-antigen that maturing T cells are tested against during negative selection.

· T cells that bind too tightly to the antigen/MHC complexes will be given a death signal and undergo apoptosis.

· T cells that bind the antigen/MHC complexes will be given a survival signal and released from the thymus.

· What about T cells that get past this checkpoint of negative selection and are released into the periphery even though they react with self-antigen?

· T cells that enter circulation even though they are self reactive will receive a signal to become inactivated (suppressed) or activated but die very soon after activation.

· (Fig. 7.19) A major player in this regulation is a special subset of CD4 T cells, call regulatory T cells (Treg).

· Tregs are reactive to self-antigen and distinguished from other CD4 T cells by the expression of CD25.

· Tregs are released into circulation from the thymus. These cells bind to self-antigen presented by MHC II on a variety of cell types. Instead of proliferating upon activation by antigen, Tregs remain bound to the antigen-presenting cell and suppress the activation of any normal CD4 T cells that also bind self-antigen on the antigen presenting cell.