**2.2 Thymopoiesis: the result of cross-talk between thymic stromal cells and precursor T cells**

T cell progenitors that lack both CD4 and CD8 receptors are termed as doublenegative (DN) cells. These cells separate from the bone marrow, enter the thymus through the large venules located at the corticomedullary junction (CMJ), and settle into the cortex of the thymus. In the thymic cortex, the rearrangement at T cell receptor (TCR) α and β genes makes the cells turn into double-positive (DP) stage, when cells express both CD4 and CD8. Then, a positive selection process directs DP cells into either CD4+ or CD8+ T cells depending on their affinity for either major histocompatibility complex (MHC) protein class II or I, respectively. The thymus selects single-positive (SP) immunocompetent T cells to export them out of the thymus. In the periphery, these naïve self-restricted T cells eventually home to secondary lymphoid organs. To bear the name of its creators, i.e., thymocytes, this process of manufacturing mature functional T cells is generally recognized as thymopoiesis.

### **2.3 Thymic mechanisms of central self-tolerance**

#### *2.3.1 Positive selection takes place in the thymic cortex*

The positive selection is defined as a process through which SP T cells expressing either CD4 or CD8 are selected. The thymic cortex carries gene rearrangements that make precursor T cells co-express CD4 and CD8. These DP T cells are then engaged by a ligand bound to an MHC class II or I molecule that is present on cTECs and will be differentiated into SP T cells that express either CD4 or CD8, correspondingly [6].

#### *2.3.2 Negative selection takes place in the thymic medulla*

The negative selection is simply a process by which autoreactive T cells are removed. After positive selection is done, the transfer of SP T cells from the cortex to the medulla occurs. The expression of chemokine receptor CCR7 by T cells is

**3**

*Introductory Chapter: Thymus - The Central Self-Tolerance System*

reactive to self to shift from the thymus to the periphery [6].

*2.3.3 Agonist selection takes place in the thymic medulla*

consequently regulates inflammatory responses [6].

**3.1 The effects of thymic infection on thymopoiesis**

**does not work?**

*3.1.1 The thymus gets sick*

essential to the transfer process—since antigen-presenting cells (APCs) including mTECs and dendritic cells in the medulla express CCR7 ligands, e.g., CCL19 and CCL21. In this manner, SP T cells can engage in interaction with medullary APCs that present a variety of tissue-restricted antigens (TRAs). Medullary APCs are responsible for finding autoreactive T cells that recognize self-antigen—MHC complexes and their removal. Such selection would permit SP T cells that are not

The agonist selection is also undertaken by the thymic medulla to allow a portion

of autoreactive CD4+ T cells to differentiate into regulatory T (Treg) cells that express forkhead box P3 (Foxp3). These regulatory T cells that are derived from the thymus are referred to as tTreg cells and move from the thymus to the peripheral tissues. They constitute the majority of all Treg cells and play the central role in immune tolerance. So, the thymus must be precisely effective in the generation of Treg cells. If this could not be achieved, then we see the process of autoimmunity. However, there are Treg cells derived from peripheral tissues referred to as pTreg cells. This type of Treg cells is especially accumulated at sites of inflammation and

**3. If peace is in the hands of the thymus, then what would happen if that** 

The thymus-mediated effects including the production of neuropeptides and also development of T cell repertoire are what may be called the function of the pacemaker [7]. However, the thymus is vulnerable to be exposed to both acute and chronic injuries. A variety of pathological conditions that range from infections and immunodeficiency to inflammatory and autoimmune disorders and tumors may cause the thymus to turn into malfunctioning or functionless. In a broader sense, the thymus undergoes physiological changes that occur with age and during pregnancy. Below is to represent dysregulation of immune homeostasis as the inevitable

consequence of a failure in central self-tolerance system, i.e., the thymus.

The thymus is not immune-privileged, but rather invading pathogens can adversely affect its structure and/or function, thymopoiesis, through indirect (systemic) and direct (local) ways. Pathogens that are able to penetrate into the different thymic location(s), e.g., cortex, CMJ, or medulla, and thereby directly infect thymic cells, include a number of viruses (human immunodeficiency virus, *Simian immunodeficiency virus*, influenza virus, lymphocytic choriomeningitis virus, *Murine leukemia virus*, mouse hepatitis virus, human cytomegalovirus, measles virus, coxsackievirus, Epstein-Barr virus, Junin virus, and poliovirus), bacteria (*Mycobacterium avium*, *Mycobacterium tuberculosis*, *Francisella tularensis*, and *Salmonella enterica*), fungi (*Paracoccidioides brasiliensis* and *Cryptococcus neoformans*), and parasites (*Trypanosoma cruzi*, *Plasmodium berghei*, and *Toxoplasma gondii*). In addition, pathogens can act indirectly by altering the systemic expression of glucocorticoids, cytokines, chemokines, and antigens. Then, these soluble factors can reach the village

of the thymus and readily result in changes of its microenvironment [8].

*DOI: http://dx.doi.org/10.5772/intechopen.90491*

*Introductory Chapter: Thymus - The Central Self-Tolerance System DOI: http://dx.doi.org/10.5772/intechopen.90491*

*Thymus*

**2.1 Immunological tolerance**

*2.1.1 Central tolerance*

*2.1.2 Peripheral tolerance*

helplessness, and suppression.

**2.3 Thymic mechanisms of central self-tolerance**

*2.3.1 Positive selection takes place in the thymic cortex*

*2.3.2 Negative selection takes place in the thymic medulla*

**precursor T cells**

**2. How does the thymus teach T lymphocytes self-tolerance?**

To keep the body healthy, the immune system is expected to entail invading pathogens while avoiding reactivity to self-tissues. This so-called immunological tolerance engages both central and peripheral modes of action (for review, see [5]).

It is referred to immature B and T cells when they are present in the primary lymphoid organs—B cells in the bone marrow and T cells in the thymus. Mechanisms of central tolerance are, for example, clonal deletion and elimination of self-reactive cells.

This one is for mature B and T cells as detached from the primary lymphoid organs into the bloodstream, lymph, and secondary lymphoid organs such as spleen and lymph nodes. There are various mechanisms that can promote tolerance in the periphery, including clonal deletion, clonal anergy, clonal ignorance, deviation,

**2.2 Thymopoiesis: the result of cross-talk between thymic stromal cells and** 

T cell progenitors that lack both CD4 and CD8 receptors are termed as doublenegative (DN) cells. These cells separate from the bone marrow, enter the thymus through the large venules located at the corticomedullary junction (CMJ), and settle into the cortex of the thymus. In the thymic cortex, the rearrangement at T cell receptor (TCR) α and β genes makes the cells turn into double-positive (DP) stage, when cells express both CD4 and CD8. Then, a positive selection process directs DP cells into either CD4+ or CD8+ T cells depending on their affinity for either major histocompatibility complex (MHC) protein class II or I, respectively. The thymus selects single-positive (SP) immunocompetent T cells to export them out of the thymus. In the periphery, these naïve self-restricted T cells eventually home to secondary lymphoid organs. To bear the name of its creators, i.e., thymocytes, this process of manufacturing mature functional T cells is generally recognized as thymopoiesis.

The positive selection is defined as a process through which SP T cells expressing either CD4 or CD8 are selected. The thymic cortex carries gene rearrangements that make precursor T cells co-express CD4 and CD8. These DP T cells are then engaged by a ligand bound to an MHC class II or I molecule that is present on cTECs and will be differentiated into SP T cells that express either CD4 or CD8, correspondingly [6].

The negative selection is simply a process by which autoreactive T cells are removed. After positive selection is done, the transfer of SP T cells from the cortex to the medulla occurs. The expression of chemokine receptor CCR7 by T cells is

**2**

essential to the transfer process—since antigen-presenting cells (APCs) including mTECs and dendritic cells in the medulla express CCR7 ligands, e.g., CCL19 and CCL21. In this manner, SP T cells can engage in interaction with medullary APCs that present a variety of tissue-restricted antigens (TRAs). Medullary APCs are responsible for finding autoreactive T cells that recognize self-antigen—MHC complexes and their removal. Such selection would permit SP T cells that are not reactive to self to shift from the thymus to the periphery [6].
