IMM: T Cell Development

T-Cell Development

1) TCR gene rearrangement 2) Selection of T cells that express TCRs that recognize peptides in the context of self MHC molecules - Positive Selection 3) Elimination of T cells that express TCRs with an affinity for self peptides plus self MHC - Negative Selection Once T cells have successfully rearranged and expressed a their receptors their development is considered complete. Bone marrow (precursor) -> Thymus (mature) -> Secondary lymphoid organs (lymph node/ spleen)

Thymocyte

A developing T cell that resides in the thymus

DiGeorge's syndrome

A genetic deficiency in humans in which the thymus fails to develop properly and there is severe immunodeficiency.

DP (Double positive) thymocytes

After signaling from the pre-TCR, these a proliferative burst is initiated and these cells are induced to express both CD4 and CD8 on the cell surface. These recognize self MHC and receive survival signals. Cells that do not recognize self MHC die by apoptosis Following the proliferative burst, TCR rearrangement at TCRα, γ and δ loci is activated, but specifically not TCRβ.

Cortiomedullary junction of Thymus

At this location, dendritic cells build up to present self-antigen (transcribed from AIRE) to maturing T cells. If T cells recognize this self-antigen, they are instructed to die. This is a checkpoint in T cell development.

CD44

Cell surface marker that are used to define different subpopulations of CD4-CD8- DN thymocytes. "+" in Early T cell development then "low" with maturation.

CD25

Cell surface marker that are used to define different subpopulations of CD4-CD8- DN thymocytes. - in early T cell development then "+" with maturation.

Negative Selection

Deletion of developing T cells that express receptors with high affinity for self MHC plus self peptide. Mediated mostly by bone marrow-derived dendritic cells and macrophages in the medulla and at the cortico-medullary junction. The selected thymocytes die by apoptosis.

AIRE (Autoimmune disease regulator)

Drives expression of tissue-specific proteins in stromal cells of thymus medulla.

Secondary rearrangement

Following the commitment to a β lineage, for example, this can happen in γ and δ chain genes at this point provides a second opportunity to commit to the γδ lineage However, in the majority of cases productive a chain rearrangement occurs first resulting in the expression of an αβ TCR and commitment to this lineage.

T cell selection

In all individuals enough different TCRαβ receptors are produced during T cell development to allow recognition of each of the different MHC molecules that occur in the population in combination with peptide. Developing T cells that do not undergo this process (the majority) die by apoptosis and are engulfed by macrophages.

Thymus

Organ comprised of developing T cells known as thymocytes in a network of epithelial cells known as the thymic stroma. outer cortical region cells are densely packed with macrophages and immature T cells. inner medulla region cells are loosely packed. contains dendritic cells (from bone marrow precursors), macrophages, mature T cells. It is most active in early life - adolescent involution (shrinking) - a process that is complete by age 30. Adults don't need it, so can cut it out.

Irradiation and chemotherapy

Prior to bone marrow transplantation, one must undergo this process to kill all of your lymphocytes. This may prevent interaction between your lymphocytes and donor lymphocytes. It allows donor lymphocytes to take over.

TCRα gene

Productive rearrangement here does not necessarily lead to the cessation of additional chain rearrangement on the same or the homologous chromosome.

Apoptosis

Programmed cell death

Positive Selection

Selection of developing T cells that have TCRs with high affinity and specificity for self MHC plus peptide are allowed to mature further. This accounts for MHC restriction. Mediated by epithelial cells in the cortex which present MHC class I and II. In this process, CD4+CD8+ double-positive thymocytes mature to CD4+ or CD8+ single-positive thymocytes. This finally stops recombination at the TCRα locus. This mechanism allows the developing T cell multiple attempts at generating TCRs that recognize self MHC. Note: If allowed to enter the peripheral circulation at this stage these T cells could recognize and respond to self antigens and cause autoimmune disease.

HLA haplotype matching

Successful bone marrow transplantation usually requires the sharing of at least one MHC class I and one MHC class II allele between donor and recipient.

Treg (T regulatory cell)

TCR-expressing T cells that arise in the thymus in response to recognition of self peptide and MHC. These cells are involved in shutting down immune responses after they have successfully eliminated invading organisms in the peripheral immune system, and also in preventing autoimmunity. Ex. FoxP3+, CD4+, CD25+

Thymic stroma

The network of epithelial cells in the thymus

Mature T cells

These are single positive T cells that have passed through the gauntlet of positive and negative selection leave the thymus, and populate the T cell areas of secondary lymphoid organs. Recirculate between secondary lymphoid organs via lymphatics and blood vessels until encounter with foreign antigen. Note: In response to antigenic challenge, CD4+ and CD8+ T cells further differentiate into different types of effector T cell that aid in removal of foreign antigens from the host

TCRαβ

These are the most common cells due to many V, J/V, D, J regions, which increases the chance of productive rearrangements and committing to this lineage. Later in development, these cells predominate and all the T cells that are produced at this point populate all peripheral lymphoid organs.

SP (single positive) thymocytes

These cells are include CD4+CD8- and CD4-CD8+ thymocytes. They are the mature form of T cells that respond to corresponding MHC classes (I->CD8, II->CD4). Finally, these mature T cells leave the thymus, and populate the T cell areas of secondary lymphoid organs.

TCRγδ

These cells can be made through rearrangement and lineage commitment. They are also generated in a separate developmental pathway very early in embryonic development. Early in development, these cells populate the reproductive and gastrointestinal tracts and skin. They do not recognize MHC/peptide complexes and their function is largely unknown. These are less common because there are fewer V, J/ V, D, J regions, so less chance for productive rearrangement.

DN (Double negative) thymocytes

These early T cells do not express the CD4 or CD8 co-receptors. They mature through CD44+CD25-, CD44+CD25+ and CD44lowCD25+ stages

MHC class II BLS (bare lymphocyte syndrome)

These patients cannot make CD4+ T cells. e.g. CIITA deficiency

MHC class I BLS (bare lymphocyte syndrome)

These patients cannot make CD8+ T cells. e.g. TAP transporter deficiency

Primary rearrangement

This determines whether a TCR commits to the αβ or γδ lineage. TCRβ gene is most common with the pre-T cell receptor alpha chain (preTα) - The pre-TCR is formed.

T cell leukemia

This is a cancer of the T cells. It begins when normal blood cells change and grow uncontrollably. Most develop from *early T cell progenitors or mature T cells*.

APECED (Autoimmune polyendocrinopathy-candidiasis ectodermal dystrophy)

This is caused by mutations in human AIRE (autoimmune disease regulator). It is a genetic autoimmune disease with an extraordinary array of clinical features but characterized most often by at least 2 of the following 3 findings: hypoparathyroidism -- underfunction of the parathyroid glands which control calcium, candidiasis (yeast infection), and adrenal insufficiency (underfunction of the adrenal gland).

preTCR

This signals to prevent further rearrangement of TCR genes. It is made of TCRβ in complex with an invariant pre-TCRα chain (pTα)

CD44lowCD25+ stage

This stage in early T cell development signals rearrangement of TCRβ, γ, δ is initiated.

TCRβ gene

Unproductive rearrangements here can be rescued by a second rearrangement.