Tcell receptor gene rearrangements and phenotypic changes

Bone marrow-derived T-cell progenitors (prothymocytes) seed the subcapsular region of the thymic lobule (Figure 20.8). At this stage of ontogeny the cells have not started to rearrange their TCR genes, do not express the mature T-cell markers CD3, CD4 or CD8, and may not be irreversibly committed to the T-cell lineage. They may be identified by expression of CD7 and CD34. Interaction with the thymic stroma is accompanied by proliferation and expression of CD2, soon followed by cytoplasmic expression of CD3 genes. By this stage, the cell is committed to the T-cell lineage and TCR gene rearrangement is under way.

The configuration of the TCR and its genes is discussed in the section on antigen-specific receptors on T and B cells and is summarized in Figure 20.4 and Table 20.1. During early fetal development, the first cells to leave the thymus as mature T cells have successfully rearranged their y and 8 genes and express the y8 form of the TCR. Many y8 T cells do not express CD8 or CD4, cells, these rearrangements require RAG1 and RAG2 genes to be expressed, and junctional diversity is increased by the addition of N sequences using tdt. Selection occurs at the double-positive stage when the full TCR complex is expressed with CD3 and both CD4 and CD8. These cells are selected on their ability to recognize self peptide presented by a self MHC molecule at low avidity. Those cells recognizing peptide with class I go on to become singlepositive CD8 expressors; those recognizing peptide with class II continue to express CD4 without CD8. Cells recognizing self peptide at high avidity and cells failing to recognize a self MHC molecule are deleted.

T-cell precursor sCD34, CD7

T-cell precursor sCD34, CD7

Blood

Virgin T cell sCD3/TCR aß sCD4 or CD8 sCD2, CD7 sCD5, CD45RA

Virgin T cell sCD3/TCR aß sCD4 or CD8 sCD2, CD7 sCD5, CD45RA

Proliferation TCR gene rearrangement

Prothymocyte

Prothymocyte

Thymic cortex

Thymic medulla

Thymic cortex

Thymic medulla

Double-positive thymocytes

Interaction between surface TCR and MHC initiates both positive and negative selection

Single-positive thymocytes Also sCD2, CD5, CD7 and CD45RO

Double-positive thymocytes

Interaction between surface TCR and MHC initiates both positive and negative selection

Single-positive thymocytes Also sCD2, CD5, CD7 and CD45RO

suggesting they may not be interacting with antigen in association with MHC class I or class II molecules. During fetal development of mice, sequential waves of y8 T cells populate different epithelial surfaces with different and restricted Vy gene usage. This does not appear to be the case in humans, although considerably less is known about the ontogeny and function of y8 T cells in humans. Some y8 T cells develop in congenitally athymic animals and are probably thymus independent and may have different functions from those of thymus-processed cells. During later stages of human fetal development and throughout the rest of life, 85-98% of T cells that leave the thymus have undergone successful a and P-gene rearrangement and express the aP TCR.

Rearrangement of the gene encoding the TCR P-chain occurs first with D to J rearrangements followed by V to D-J rearrangements. Successful rearrangement leads to low-level expression of the P-chain at the cell surface in a complex with CD3 and a surrogate a-chain analogous to X5-V-pre-B in B-cell development. It is at this stage that the cell starts to express low levels of both CD4 and CD8; further P-chain gene rearrangement is halted and a-chain gene rearrangement starts (Figure 20.8). TCR a-chain gene rearrangement may involve sequential rearrangements of V-J pairs, which enables the cell to express different TCR a-chains until a successful TCR aP heterodimer is generated. Unlike B cells, aP T cells do not show allelic exclusion of TCR a-chains and approximately 30% of peripheral T cells have two functional TCR a-chain rearrangements. Both may be expressed at the cell surface such that a small proportion of T cells may express two different antigen receptors.

Selection of the TCR ap T-cell receptor repertoire

CD8 and CD4 thymocytes are selected on the basis of their potential to recognize peptides held in association with either MHC class I or MHC class II molecules respectively. Immature aP TCR thymocytes are subject to two selection processes -positive selection, which allows cells that have the potential to recognize foreign peptide in association with self-MHC to mature to functional T cells, and negative selection, which removes T cells that recognize self-peptides in association with a self-MHC molecule. As with B cells, exhaustion of this process without successful rearrangement results in cell death by apoptosis. Generation of a rearrangement that is positively selected by interaction with self-MHC is accompanied by cessation of further gene rearrangement, loss of RAG1, RAG2 and tdt expression and cessation of expression of the redundant CD4 or CD8 molecule. Although the selection forces that are imposed on aP T cells are well defined, it is still unclear whether those y8 T cells that develop in the thymus undergo a similar selection process.

Overt and hidden self peptides

It is now clear that negative selection in the thymus does not cover all the peptides produced from proteins within the body. This applies particularly to intracellular proteins and to extracel lular proteins in tissues that do not normally allow the egress of macromolecules, such as the anterior chamber of the eye. These proteins may therefore be immunogenic if administered system-ically in an appropriate form.

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