Positive And Negative T Cell Selection

T cell selection is a crucial process in the thymus that ensures the immune system can effectively recognize and respond to foreign antigens while avoiding self-reactivity. This intricate process involves both positive and negative selection, each playing a distinct role in shaping the T cell repertoire. Understanding these mechanisms is essential for comprehending the development of a functional and self-tolerant immune system.

The Importance of T Cell Selection

T cells, a type of lymphocyte, are central to adaptive immunity. They recognize antigens presented by antigen-presenting cells (APCs) via the major histocompatibility complex (MHC). However, the generation of T cells is a random process, meaning that some T cells may not recognize MHC molecules at all, while others may react against the body's own tissues, leading to autoimmunity.

T cell selection in the thymus eliminates these potentially harmful or non-functional T cells, ensuring that only T cells that can recognize foreign antigens without attacking self-antigens are released into the periphery. This selection process involves two main stages: positive selection and negative selection.

Overview of T Cell Development in the Thymus

T cell development begins in the bone marrow, where hematopoietic stem cells differentiate into lymphoid progenitor cells. These progenitor cells then migrate to the thymus, a specialized organ in the chest, where they undergo a series of developmental stages known as thymopoiesis.

Thymic Structure

The thymus is divided into two main regions: the cortex and the medulla.

• Cortex: The outer region of the thymus where T cell precursors, known as thymocytes, undergo positive selection.
• Medulla: The inner region where thymocytes undergo negative selection.

Stages of T Cell Development

1. Double-Negative (DN) Stage: Thymocytes enter the thymus as double-negative (DN) cells, meaning they do not express either the CD4 or CD8 co-receptor.
2. Double-Positive (DP) Stage: DN cells proliferate and differentiate into double-positive (DP) thymocytes, expressing both CD4 and CD8 co-receptors.
3. Positive Selection: DP thymocytes interact with cortical thymic epithelial cells (cTECs) expressing MHC class I and MHC class II molecules.
4. Lineage Commitment: DP thymocytes that successfully undergo positive selection downregulate either the CD4 or CD8 co-receptor, becoming either CD4+ or CD8+ single-positive (SP) thymocytes.
5. Negative Selection: SP thymocytes interact with medullary thymic epithelial cells (mTECs) and other APCs expressing self-antigens.
6. T Cell Export: SP thymocytes that survive negative selection are exported to the periphery as mature, naïve T cells.

Positive Selection: Recognizing Self-MHC

Positive selection is the first critical step in T cell selection. It ensures that developing T cells can recognize and bind to MHC molecules. This process occurs in the thymic cortex and involves interactions between DP thymocytes and cortical thymic epithelial cells (cTECs).

The Role of Cortical Thymic Epithelial Cells (cTECs)

cTECs express both MHC class I and MHC class II molecules on their surface. These MHC molecules present self-peptides, allowing DP thymocytes to test their ability to bind to MHC.

Mechanism of Positive Selection

1. MHC Interaction: DP thymocytes express a diverse repertoire of T cell receptors (TCRs) generated through V(D)J recombination. These TCRs randomly rearrange genes to create unique antigen-binding sites.
2. TCR Binding: DP thymocytes interact with MHC molecules on cTECs. If the TCR on a DP thymocyte binds to an MHC molecule with a certain affinity, the thymocyte receives a survival signal.
3. Survival Signal: The survival signal, primarily mediated by the co-stimulatory molecule CD28 and downstream signaling pathways, prevents the thymocyte from undergoing programmed cell death (apoptosis).
4. Failure to Bind: DP thymocytes that fail to bind to MHC molecules on cTECs do not receive a survival signal and undergo apoptosis. This process is often referred to as "death by neglect."
5. Lineage Commitment: DP thymocytes that successfully bind to MHC molecules are positively selected and proceed to lineage commitment.

Lineage Commitment: CD4+ vs. CD8+

After positive selection, DP thymocytes commit to becoming either CD4+ or CD8+ single-positive (SP) T cells. This lineage commitment is determined by the class of MHC molecule that the TCR binds to during positive selection.

• MHC Class II Binding: If the TCR binds to MHC class II molecules, the thymocyte downregulates the expression of CD8 and becomes a CD4+ T cell. CD4+ T cells typically function as helper T cells, assisting in activating other immune cells.
• MHC Class I Binding: If the TCR binds to MHC class I molecules, the thymocyte downregulates the expression of CD4 and becomes a CD8+ T cell. CD8+ T cells typically function as cytotoxic T cells, killing infected or cancerous cells.

The precise mechanisms that control lineage commitment are still under investigation, but several models have been proposed.

• Instructive Model: The strength and duration of TCR signaling determine lineage commitment. Strong and sustained signaling through MHC class II molecules drives CD4+ T cell development, while weaker or shorter signaling through MHC class I molecules drives CD8+ T cell development.
• Stochastic Model: Lineage commitment is a random process. DP thymocytes randomly downregulate either CD4 or CD8, and only those that match the MHC specificity of their TCR survive.
• Kinetic Signaling Model: The kinetic signaling model suggests that the duration of TCR signaling determines lineage commitment. Sustained signaling favors CD4+ T cell development, while interrupted or transient signaling favors CD8+ T cell development.

Negative Selection: Eliminating Self-Reactive T Cells

Negative selection is the second critical step in T cell selection. It eliminates T cells that react strongly to self-antigens, preventing autoimmunity. This process primarily occurs in the thymic medulla and involves interactions between SP thymocytes and medullary thymic epithelial cells (mTECs) and other antigen-presenting cells (APCs).

The Role of Medullary Thymic Epithelial Cells (mTECs)

mTECs play a unique role in negative selection due to their expression of a wide range of tissue-specific antigens (TSAs). This expression is controlled by the autoimmune regulator (AIRE) gene.

• AIRE Gene: The AIRE gene promotes the expression of thousands of TSAs in mTECs, allowing developing T cells to be exposed to a diverse array of self-antigens. This ensures that T cells with reactivity to antigens expressed in peripheral tissues are eliminated in the thymus.

Mechanism of Negative Selection

1. Self-Antigen Presentation: SP thymocytes migrate to the thymic medulla, where they encounter mTECs and other APCs presenting self-antigens on MHC class I and MHC class II molecules.
2. TCR Binding: SP thymocytes interact with self-antigen-MHC complexes on mTECs and APCs. If the TCR on a thymocyte binds to a self-antigen-MHC complex with high affinity, the thymocyte receives a death signal.
3. Apoptosis: The death signal, primarily mediated by activation of the Fas receptor and downstream signaling pathways, triggers apoptosis in the thymocyte.
4. Central Tolerance: Negative selection is a key mechanism of central tolerance, ensuring that the immune system does not react against self-antigens.

Outcomes of Negative Selection

• Deletion: The most common outcome of negative selection is apoptosis, leading to the physical elimination of self-reactive T cells.
• Receptor Editing: Some self-reactive T cells can undergo receptor editing, a process in which they rearrange their TCR genes to change the specificity of their TCR. If receptor editing results in a TCR that is no longer self-reactive, the T cell can survive.
• Development of Regulatory T Cells (Tregs): A subset of self-reactive T cells can differentiate into regulatory T cells (Tregs). Tregs play a crucial role in maintaining peripheral tolerance by suppressing the activity of other T cells.

Factors Influencing Negative Selection

• Affinity of TCR for Self-Antigen: The strength of the interaction between the TCR and the self-antigen-MHC complex is a critical determinant of negative selection. High-affinity interactions typically lead to apoptosis, while lower-affinity interactions may result in survival or differentiation into Tregs.
• Concentration of Self-Antigen: The concentration of self-antigen presented by mTECs and APCs can also influence negative selection. Higher concentrations of self-antigen may lead to more efficient deletion of self-reactive T cells.
• Co-stimulatory Signals: The presence or absence of co-stimulatory signals can modulate the outcome of negative selection. Co-stimulation can enhance the death signal, while the absence of co-stimulation may promote the development of Tregs.

The Role of Antigen-Presenting Cells (APCs) in T Cell Selection

Antigen-presenting cells (APCs) play a crucial role in both positive and negative selection by presenting antigens to developing T cells.

Cortical Thymic Epithelial Cells (cTECs)

cTECs are the primary APCs involved in positive selection. They express MHC class I and MHC class II molecules and present self-peptides to DP thymocytes, allowing them to test their ability to bind to MHC.

Medullary Thymic Epithelial Cells (mTECs)

mTECs are the primary APCs involved in negative selection. They express a wide range of tissue-specific antigens (TSAs) under the control of the AIRE gene, allowing developing T cells to be exposed to a diverse array of self-antigens.

Dendritic Cells (DCs)

Dendritic cells (DCs) are professional APCs that play a role in both positive and negative selection. They can migrate to the thymus from the periphery and present self-antigens acquired from peripheral tissues. DCs can also present antigens derived from thymic cells, contributing to the deletion of T cells reactive to thymic-specific antigens.

Macrophages

Macrophages are phagocytic cells that can also function as APCs. They can present self-antigens to developing T cells and contribute to negative selection. Macrophages also play a role in clearing apoptotic cells in the thymus.

Consequences of Defective T Cell Selection

Defects in T cell selection can have severe consequences for the immune system, leading to autoimmunity or immunodeficiency.

Autoimmunity

Failure of negative selection can result in the survival of self-reactive T cells, leading to autoimmune diseases. These self-reactive T cells can attack the body's own tissues, causing chronic inflammation and tissue damage.

• Type 1 Diabetes: In type 1 diabetes, self-reactive T cells attack the insulin-producing beta cells in the pancreas, leading to insulin deficiency.
• Multiple Sclerosis: In multiple sclerosis, self-reactive T cells attack the myelin sheath that protects nerve fibers in the brain and spinal cord, leading to neurological symptoms.
• Rheumatoid Arthritis: In rheumatoid arthritis, self-reactive T cells attack the joints, causing chronic inflammation and joint damage.

Immunodeficiency

Defects in positive selection can result in a reduced T cell repertoire, leading to immunodeficiency. A limited T cell repertoire may not be able to effectively respond to a wide range of pathogens, increasing susceptibility to infections.

• Severe Combined Immunodeficiency (SCID): SCID is a group of genetic disorders characterized by a complete or partial absence of functional T cells and B cells. Defects in genes involved in T cell development, such as RAG1 and RAG2, can lead to SCID.
• DiGeorge Syndrome: DiGeorge syndrome is a genetic disorder caused by a deletion on chromosome 22. It results in the underdevelopment or absence of the thymus, leading to a reduced T cell repertoire and increased susceptibility to infections.

Clinical Significance of T Cell Selection

Understanding the mechanisms of T cell selection is crucial for developing new therapies for autoimmune diseases and immunodeficiency disorders.

Immunotherapies for Autoimmune Diseases

• Targeting Self-Reactive T Cells: Immunotherapies that selectively eliminate or suppress self-reactive T cells could be used to treat autoimmune diseases. This could be achieved by targeting specific TCRs or by using drugs that promote apoptosis in self-reactive T cells.
• Enhancing Treg Function: Therapies that enhance the function of regulatory T cells (Tregs) could be used to suppress the activity of self-reactive T cells and restore immune tolerance.

Immunotherapies for Immunodeficiency Disorders

• Thymic Transplantation: Thymic transplantation can be used to restore T cell function in patients with thymic deficiencies, such as DiGeorge syndrome.
• Gene Therapy: Gene therapy can be used to correct genetic defects that impair T cell development, such as mutations in RAG1 or RAG2.

Conclusion

Positive and negative T cell selection are essential processes for establishing a functional and self-tolerant immune system. Positive selection ensures that T cells can recognize MHC molecules, while negative selection eliminates self-reactive T cells. Defects in these processes can lead to autoimmunity or immunodeficiency. A deeper understanding of the mechanisms of T cell selection is crucial for developing new therapies for immune-related disorders. By elucidating the intricate details of these processes, researchers can pave the way for more effective and targeted treatments that harness the power of the immune system while preventing its harmful effects.