T Cells and Thymus Development

Early T cell development starts with precursor cells called CLPs (common lymphoid progenitors), which are produced in the bone marrow. These CLPs then migrate to the thymus, driven by the attraction of the chemokine receptor CCR9.

T cell development in the thymus involves multiple stages, ensuring only properly functioning T cells are released into the body. These stages are characterized by changes in the expression of CD4 and CD8 proteins. This process involves "quality control" to eliminate harmful T cells.

Once T cells have matured in the thymus, they exit and travel to peripheral lymphoid organs like lymph nodes and spleen. From there, they can migrate to different tissues in the body based on need.

The T cell receptor (TCR) is a surface protein that recognizes and binds to antigens, triggering the immune response. TCR development involves two main stages: first the TCR beta chain is assembled, followed by the TCR alpha chain. The expression of each chain is part of the quality control during T cell development.

Before a functional TCR alpha chain is formed in the thymus, the TCR beta chain can form a pre-receptor complex with a protein called pre-T alpha. This pre-TCR complex helps ensure that the TCR beta chain is correctly assembled and helps regulate further development of T cells.

During T cell development, the cells are classified based on their expression of the CD4 and CD8 co-receptors: Double negative (DN): neither CD4 nor CD8 expressed; Double positive (DP): both CD4 and CD8 expressed; Single positive (SP): either CD4 or CD8 expressed . This classification is important to track the maturation process of a T cell.

Double positive (DP) thymocytes express both CD4 and CD8, while single positive (SP) thymocytes express only one of them. This change in co-receptor expression is essential for the final differentiation of T cells into either CD4+ helper T cells (CD4 single positive) or CD8+ cytotoxic T cells (CD8 single positive).

Gamma delta (γδ) T cells are a smaller subset of T cells than conventional alpha beta (αβ) T cells and have a different TCR structure. They play a role in innate immunity and respond to a variety of stimuli. During thymocyte development, mature γδ T cells are formed and become functional, which prevents the further rearrangement of alpha beta TCR, ensuring the final fate of the T cell.

VDJ recombination follows the 12-23 rule, which states that a recombination signal sequence (RSS) with a 12-base pair spacer can only recombine with an RSS containing a 23-base pair spacer.

Recombination signal sequences (RSS) are short DNA motifs located adjacent to variable (V), diversity (D) and joining (J) gene segments in the immunoglobulin gene locus. They are crucial for the proper assembly of antibody genes during VDJ recombination.

A spacer is a non-coding DNA region between the heptamer and nonamer sequences of a recombination signal sequence (RSS). Its length (12 or 23 base pairs) is crucial for the 12-23 rule, ensuring proper VDJ recombination.

The 23-base pair spacer within an RSS contributes to the bending of the DNA molecule. This bending is essential for the proper alignment and interaction of the two RSSs during VDJ recombination.

RAG1 and RAG2 are DNA recombinases that play a crucial role in VDJ recombination. They bind to RSSs, bring together the 12nt and 23nt sequences, and cleave the DNA, initiating the recombination process.

After RAG1/2 cleavage, the DNA double-strand breaks are stabilized by Ku70 and Ku80. DNA-PK repairs the broken ends by opening the hairpin, allowing for the addition of N nucleotides by TdT (terminal deoxynucleotidyl transferase) to the open ends. Finally, DNA ligase IV and XRCC4 ligate the ends together forming a coding joint.

P-nucleotides arise during the repair process of VDJ recombination, where the hairpin structure is opened. These nucleotides are incorporated into the coding joint region due to the filling of gaps by DNA polymerase. They add to the diversity of the antibody repertoire.

N-nucleotides are non-templated nucleotides randomly added to the coding joint region by the terminal deoxynucleotidyl transferase (TdT) enzyme, increasing the diversity of the antibody repertoire. This random addition contributes to the vast diversity of antibody genes generated during VDJ recombination.

A second signal needed for T cell activation, provided by molecules like B7 on APCs, binds to CD28 on T cells. This signal helps ensure the T cell response is appropriate and avoids accidental activation.

The third signal for T cell activation, provided by cytokines like IL-2, is essential for proliferation and differentiation of the T cell.

A state of unresponsiveness in T cells when they receive only Signal 1 (antigen recognition) without Signal 2 (costimulation). The T cell essentially becomes inactive.

A family of proteins that act as key signaling molecules in T cell activation. They are highly conserved in various immune cells.

A crucial enzyme involved in T cell signaling. It is stimulated by Signal 1 and helps activate other signaling molecules.

A key protein involved in T cell activation. It's a transcription factor, meaning it can switch genes on or off in the cell.

A process involving the recognition of antigens by the TCR and the subsequent activation of T cells, leading to an immune response.

A vital growth factor for T cells, crucial for their proliferation and survival. It is produced by activated T cells themselves and promotes their expansion.

A state of unresponsiveness or inactivation in T cells, caused by the lack of co-stimulatory signals during antigen presentation. It prevents T cells from becoming hyperactive and potentially causing autoimmune reactions.

An organized structure formed at the interface between a T cell and an antigen-presenting cell (APC), facilitating efficient communication and signal exchange.

The central region of the immunological synapse, enriched in TCRs, signaling molecules, and adhesion molecules, facilitating signal transduction and T cell activation.

A type of T cell responsible for killing infected cells and tumor cells. They are activated by antigen presentation on MHC-I and release cytotoxic molecules such as perforin, granzyme B, and FasL.

A protein released by CD8+ T cells that creates pores in the target cell membrane, allowing entry of other cytotoxic molecules.

A protease released by CD8+ T cells that enters target cells through perforin-created pores and triggers apoptosis.

A cytokine released by CD8+ T cells that enhances the killing of infected cells.

A protein released by CD8+ T cells that binds to Fas receptors on target cells, triggering apoptosis.

Lymphocytic choriomeningitis virus (LCMV) is a member of the Arenaviridae family, a group of viruses with segmented, single-stranded RNA genomes. It's found naturally in rodents and can be transmitted through bodily fluids and during birth.

LCMV is a non-cytopathic virus, meaning it doesn't directly kill cells, but it can multiply within them. This makes it harder to eliminate by the immune system.

In C57BL/6 mice (which have the H-2b MHC complex), LCMV infection triggers an immune response, with CD8 T cells targeting specific viral proteins. The most prominent targets are the GP33-41 and NP396-405 epitopes.

The immune response against LCMV in mice involves a rapid expansion of CD8 T cells, which are activated by antigen presentation. These T cells then secrete effector cytokines, which help eliminate the virus.

The LCMV infection model in mice is widely used to study CD8 T cell responses. By analyzing the kinetics of the response, researchers can learn about T cell activation, differentiation, and memory formation.

During a LCMV infection, the number of CD8 T cells specific for the viral epitopes rapidly increases, forming a peak in the response. This is followed by a contraction phase where some of the activated T cells are eliminated.

Following the contraction phase, a population of memory CD8 T cells persists. This population can respond rapidly to re-exposure to LCMV, providing protection against subsequent infections.

The LCMV infection model highlights the importance of CD8 T cells in controlling viral infections. These cells provide a crucial line of defense against pathogens, contributing to both the initial control and the long-term immunity.

T cells develop in the thymus through a process of positive and negative selection. This ensures that only T cells that recognize foreign antigens and do not attack the body's own cells are allowed to mature.

The T cell receptor (TCR) is the key protein on T cells that recognizes and binds to antigens presented by MHC molecules on antigen-presenting cells (APCs).

The TCR consists of two chains, alpha and beta (or gamma and delta in a smaller population). The CD3 complex is essential for signaling, allowing the TCR to transmit information to the cell's interior.

Naive T cells require three signals to become fully activated: Signal 1: MHC-TCR interaction (antigen recognition). Signal 2: Co-stimulation by B7-CD28 (secondary confirmation). Signal 3: Cytokine receptors (mainly IL-2) (activation).

CD8+ T cells are cytotoxic and kill cells infected with intracellular pathogens or cancer cells. They have specialized cytotoxic molecules that directly eliminate target cells upon activation.

CD4+ T cells help other immune cells by releasing cytokines. For example, they assist B cells in antibody production, activate macrophages to fight off pathogens, and assist CD8+ T cells in their killing function.

Anergy is a state of non-responsiveness in T cells when they receive only Signal 1 (antigen recognition) without Signal 2 (co-stimulation). They become inactive and cannot effectively respond to the antigen.

The function of a cell depends on its specific cytokine profile. For example, IFN-γ activates macrophages, IL-4 induces IgE production, IL-17A promotes inflammation, and TGF-β has suppressive functions.