Chapter 15: T-cell development

T cell precursors that leave bone marrow to the thymus are known as thymocytes. In thymus gland T cells undergo a selection process where thymocytes bearing TCR that can attack self antigens are eliminated or made tolerant. T-cells that will survive the selection process are those that follow this rule: TCR binds to non-self antigen + self MHC So, mature T-cells are said to be self-restricted and self-tolerant. Remember that T-cells function is called cell mediated immunity; which include: 1. Killing virally infected cells and tumor cells. 2. Activating the bactericidal functions of macrophages. 3. "Helping" B cells and CD8+ T cells to mature into effector cells, and secreting various cytokines. The thymus gland You should know now that the thymus consists of three main zones: subcapsular area, cortex, and medulla. What happens if we remove the thymus gland (i.e. thymectomy) for someone after birth? Actually, although the thymus has a critical role for T cell development, but if it was removed after birth this has only little impact on T cell population, because the T cell repertoire has already been created. Ok. Then what if, for a reason or another, all T cells in the body are killed (ex. for bone marrow transplantation)? Then the thymus gland is necessary to re-establish the T cell population. Production of T cells from bone marrow is maintained throughout life. But it decreases with age. So, in old people we depend on peripheral division of mature T cells (under the influence of IL-7) to maintain T cell numbers.
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Development of T cells in the thymus

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Double negative (DN) stage Those cells that arrive from the bone marrow. They are found in the subcapsular area of thymus gland. Called double negative because they are negative for both CD4 and CD8 They are also negative for TCR and for the T cell marker CD3 These cells show the cell surface molecules: CD44 and CD25 Commitment to one cell lineage: In this stage the T cell chooses one line; or T cell.

Note: CD44 is an adhesion molecule. CD25 is the chain of IL-2 receptor. They are expressed only in the DN stage. 2.

Double positive (DP) stage DP cells are found in the cortex of thymus They express both CD4 and CD8 The mature TCR appears at this stage This is the stage where positive selection is applied. Positive selection means that only those thymocytes that can interact with self MHC (expressed by cortical epithelial cells) stay alive. Positive selection will assure that T cells are self-restricted. 95% of the T cells will not pass the positive selection, and they eventually die.

3. Single positive
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This stage occurs in the thymic medulla By this stage the developing T cell has chosen either CD4 or CD8 line. This is called lineage commitment. How does the cell choose its line? If it interacts with class I MHC (at the surface of cortical epithelial cells) it will continue to CD8+ (cytotoxic) T-cell, and the CD4 disappears. And if it interacts with Class II MHC it will continue to CD4+ (helper) T cell. So the T cells are said to be double-checked in the cortex; the first check point is the positive selection and the second check point is whether it interacts preferentially with class I or class II. Negative selection occurs at this stage. Negative selection means that T cells that interact with self peptide antigen displayed on the surface of dendritic cell by MHC molecules are deleted by apoptosis. Negative selection will assure that T cells are self-tolerant. 2/3 of cells that survive the positive selection in the cortex are deleted by negative selection in the medulla.

4. Mature nave T cell This cell will leave the thymus and will go to the periphery

Order of TCR gene rearrangement First of all, the cell should take a decision: or lineage. To do so, the and genes try to rearrange, the genes that are rearranged first will take the control and the cell will follow that line. Most of the time the gene rearranges first and the cell will commit to the lineage. If the rearrange first, then the cell will commit to this line. This step occurs in the DN stage. If the gene rearranges, it is joint with an Pre T- chain and a CD3 to form the preTCR complex. Expression of the Pre-TCR leads to:
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1. Signal transduction. 2. Signals from the pre-TCR halt further -chain rearrangements 3. Allows proliferation of the DP-T cells which promotes TCR -chain rearrangement When the cell starts to proliferate this will increase the V(D)J recombinase and causes rearrangement in the TCR gene. After rearrangement of the gene, an chain of the TCR is produced and the mature TCR complex is expressed at the surface of the DP cell along with both CD4 and CD8. Summary to the positive and negative selection As a summary, the TCR should interact with the [self peptide]-MHC complex, but if the affinity is low then the cell will die (because low affinity means that the T cell is not capable of binding to the self MHC). On the other hand cells that show high affinity will be also killed by negative selection (because high affinity means that the TCR is specific for the self peptide). So cells that will survive positive and negative selection are those that have almost intermediate affinity.

Autoimmune polyendocrine syndrome I (AR) This is an autoimmune disease that is caused by a mutation in a gene that is called autoimmune regulator gene (AIRE). This gene is responsible for regulating expression of several self antigens of many endocrine organs in the thymic epithelial cells. So a mutation in this gene will result in absence of these self antigens in thymic epithelial cells, thus, the T cells bearing TCRs that are able to bind these antigens are not negatively selected, and will go to the periphery where they will cause autoimmune disease in endocrine organs. The periphery: nave T-cell activation by antigen
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Each T cell can recognize a specific antigen; this antigen is sometimes referred to as the cognate antigen of that T cell. A nave T cell is constantly circulating between secondary lymphoid organs until they meet an APC that presents its cognate antigen. The T cell will interact with that dendritic cell and will be activated. This will result in priming of the T-cell and proliferation and differentiation into memory T cells and effector T cells. Effector T cells are short lived but they are efficient at responding to those antigens in different ways. Some of the effector T cells will migrate from the secondary lymphoid organs to periphery where they meet the antigen and finish the infection. Other primed effector T cells will go to the germinal center of follicles (the region of B cells) and help activating the appropriate B cell to produce antibodies against that antigen. Most of effector T cells then die by apoptosis after eliminating the infection, while memory T cells remain for future re-infection.

Peripheral T-cell Tolerance Not all bodys self antigens are found in the thymus, so few of the T cells leaving the thymus will have self reactivity. But there are peripheral mechanisms to induce tolerance to those cells, so that they will not cause an autoimmune disease: 1. Deletion induced tolerance: If the T cell is specific for a common self antigen, then it will be stimulated frequently by this antigen, and this will lead to cell apoptosis. 2. Clonal anergy: T cells should have a costimulatory signal to be activated. This signal is derived from an APC. If the T cell doesnt receive that signal it will become anergic.

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There is a population of T cells that are called regulatory T cells (T reg) that expresses high amount of CD25 and are capable of suppressing effector T cells by expression of IL-10 and transforming growth factor (TGF-).

Note: T reg cells depend on a transcription factor called Foxp3. A mutation in this Foxp3 will result in multisystem autoimmune disease.

CD4+ The primed (i.e. activated effector T cell) T-helper (CD4+) also called TH0 cells, can become one of two main active forms of this cell: the first is called TH1 (T helper 1) cell, and the second is called TH2 cell. Which one of the two ways it will choose is largely dependent on the cytokines in the environment. Activated macrophages will release IL-12. IL-12 will stimulate the TH0 to progress to TH1 response. TH1 cells produce large amounts of IFN-. IFN-: o A potent activator of macrophage phagocytic activity and bactericidal mechanisms. o Stimulates plasma cells to switch to IgG which is an excellent opsonin. Allergens and parasitic infections stimulate the release of IL-4 which will induce the TH0 to progress to TH2. TH2 cells produce the cytokines IL-4 and IL-5. IL-4 and IL-5: o They cause class switching toward the production of IgE o They increase production of mast cells and eosinophils CD8+ CD8+ T cells recognize antigen displayed on MHC class I molecules, and because MHC class I molecules are found on essentially all nucleated cells of the body CD8+ T cells can monitor all cells for signs of infection. Activation of CD8+ T Cells is achieved by: 1. Encountering an antigen on a professional APC and receiving activation signals from both MHC class I and costimulatory molecules (e.g., CD80 (B7)).
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2. Encountering antigen on a non-APC target cell and receiving a "second signal" from cytokines released by CD4+ T-helper cells. The T cells 1. It recognizes certain peptide and nonpeptide antigens without processing and in the absence of MHC class I or II molecules. 2. They act as a part of the first line of defense, recognizing microbial invaders in the skin and gut mucosa predominantly.

Partial Di George Syndrome

It is caused by deletion of part of chromosome 22 The structures derived from the third and fourth pharyngeal pouches do not develop in this syndrome, including the thymus and parathyroid glands. This syndrome is a combination of: 1. 2. 3. 4.
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Fistula between the esophagus and trachea. Convulsions due to low calcium levels. Subtly unusual facial appearance. Absent thymus on chest radiograph. NO cardiac defects in this syndrome.

The infant continues to develop fairly normally. He is observed to have a decreased number of CD3+T cells. However, his immunoglobulin levels are normal. He handles normal childhood infections well, and He is not provided any special immunologic treatment. By early adulthood, he is leading a normal life. Patients with complete Di George syndrome suffer from opportunistic infections (e.g., from fungi and viruses).

MHC Class II Antigen Deficiency

Autosomal-recessive condition; which is found mainly in North Africa; in which the patients' B cells (and blood monocytes) lack MHC class II molecules on the cell surface.
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 This will leads to persistent problems with viral and bacterial infections. These patients have thymic hypoplasia; and the lack of MHC class II molecules results in abnormal thymic selection processes and a block in CD4+ T-cell development.

There are normal numbers of CD8+ T cells but very low levels of CD4+ T cells. The low level of CD4+ T cells creates difficulties in providing T-helper function and this probably explains the hypogammaglobulinemia in these patients, which is present despite normal numbers of B cells. The mutations determined lie in regulatory genes that affect the expression of MHC class II genes and NOT in the MHC class II genes themselves.

Influence of the Pregnancy-induced Reduction in T-Cell Immune Responses on Multiple Sclerosis The T cells in the MS lesions are primarily of the CD4+ TH1 phenotype, and evidence shows that downregulation of the TH1 response may alleviate exacerbations. MS relapse rates were significantly decreased during the third trimester, then significantly increased at 3 months postpartum.

Acute Epstein - Barr virus Infection

In the developing world, infection takes place in early childhood, and it is usually asymptomatic. In the developed world, infection is usually delayed until adulthood, and it causes infectious mononucleosis (also known as glandular fever).

Symptoms of infectious mononucleosis (IM) include a sore throat, malaise, lymphadenopathy, and, possibly, an enlarged spleen. There may also be malignancy associated with EBV infection.
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 Acute EBV is characterized by a massive increase in the number of CD8+ T cells in the peripheral blood. The increase appears to be of EBV antigen-specific T cells.

Based on studies using a technique for enumerating virus-specific T cells, known as tetramer analysis , it has been suggested that the enormous expansion of T cells during acute EBV infection may be a result of the expansion of a few dominant clones of CD8+ T cells with specificity for EBV antigens-a so-called oligoclonal expansion. EBV infects its target cell, the B cell, for life. Thus, EBV establishes a latent infection. CD4+ T cells also respond to acute EBV infection and produce interleukin-6, interferon-, and tumor necrosis factor. An antibody response (mostly IgM), is also mounted during acute EBV; although it is not as useful in limiting this infection as the CTL response. The combination of antibody and CD8+ CTL, however, reduces, but does NOT eliminate the infection.

Finally, some of the CD4+ T and CD8+ T cells become memory cells and help in a future response to the virus.

"Sterilizing immunity" is not reached here but at least the infection has been limited by our immune system.

TAQAROB & ATYAF