Development of T lymphocytes Flashcards
Double negative
When they do not express any co receptors (thymic immigrant stage)
Double positive
Both co receptors are expressed
Single positive
Only 1 co receptor is expressed
T cells
- derive from bone marrow stem cells
- rearrange TCR genes in the thymus (antigen independent)
- formation of 2 different T cell lineages (majority alpha/beta, and minority gamma/delta)
- positive selection (alpha/beta)
- negative selection (gamma/delta)
B cells
- derive from bone marrow stem cells
- rearrange BCR genes in the BM (antigen independent)
- somatic hypermutation (antigen dependent)
Thymus
Primary lymphoid organ
- T cell development only
- blood is only route to enter (T cell progenitors) and to leave (mature T cells)
Hassall’s corpuscle
Site of cell destruction, located in the medulla of the thymus
Differences between canine and human thymus
There are none
2 types of thymus epithelial cells
- cortical (thymicorigin)
- medullary (thymicorigin)
Other cells presented in the thymus
- thymocyte (bone marrow origin)
- dendritic cell (bone marrow origin)
- macrophage (bone marrow origin)
Thymus development
- most active in very young
- fully developed at birth
- atrophies with increasing age, thymocytes replaced by fat (involution)
- involution complete by 30 years
Does involution or a thymectomy compromise T cell immunity?
No, T cells are long lived or self-renewing
Thymus involution
DiGeorge’s syndrome
- thymus fails to develop = SCIDS
- 22q11.2 deletion syndrome
Thymic cortex
- apoptotic cells
- macrophages
A common double negative T cell progenitor gives rise to _______
Alpha/beta and gamma/delta T cells
2 major signals for T cell lineage commitment
- IL-7
- Notch 1
CD34
Uncommitted progenitor
CD2
Committed double-negative T cell progenitor
Gamma + delta
Committed gamma/delta T cell
Beta lineage
Uncommitted double-positive thymocyte
- CD8 and CD4 receptors
- first checkpoint
Alpha + beta
Committed alpha/beta T cell
- CD8 and CD4 receptors expressed
- second checkpoint
- study chart in ppt*
Positive selection
Selection of T cells that can recognize peptides presented by a self-MHC molecule
- small population of T cells is signaled to mature further, leaving majority of double positive cells to die by apoptosis
- controls expression of CD4 or CD8 co receptor
Negative selection
Deletion of T cells whose antigen receptors bind too strongly to the complexes of self-peptides and self- MHC molecules presented
- negative selection cannot eliminate T cells whose receptors are specific for self peptides that are present only in tissues other than the thymus
Negative selection
Deletion of T cells whose antigen receptors bind too strongly to the complexes of self-peptides and self- MHC molecules presented
- negative selection cannot eliminate T cells whose receptors are specific for self peptides that are present only in tissues other than the thymus
AIRE
Autoimmune regulator
- mutation causes autoimmune polyglandular syndrome type 1 or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)
- Because of AIRE gene, APCs in the thymus express and present many peptides derived from nonthymic tissues
What happens if there are only thymus specific cells in the thymus?
T cells will go to periphery and be autoreactive
- AIRE gene is the safety mechanism
What is the major mechanism of immunological tolerance in the thymus?
Negative selection
Thymic epithelial cells and transcription factor
Transcription factor causes several hundred of other tissue specific genes to be transcribed by a subpopulation of the thymic epithelial cells
Mechanisms that contribute to immunological self-tolerance
Central tolerance
- negative selection in the bone marrow and thymus
- expression of tissue-specific proteins in the thymus (AIRE)
Peripheral tolerance
- no lymphocyte access to some tissues
- suppression of autoimmune responses by regulatory T cells
- induction of anergy in autoreactive B and T cells (absence of co stimulatory signal)
Mechanisms of malignant transformations and generation of lymphomas
- high division rate of maturing lymphocytes
- activity of DNA recombination mechanisms responsible for generating antigen receptor diversity
Terminally differentiated T cells retain lifelong capacity for _____
Neoplasia
Canine X-linked SCIDS
<4 weeks: greater number of B cells and CD45RA + T cells
> 8 weeks: increased B cells and T cells, decreased CD45RA+T cells
XLSCID in Basset Hounds
Cell counts: dramatically fewer T cells, but normal or above number if IgM B cells
Immunological analysis
- roles of IL-2 in T cell proliferation in the thymus and proliferation and differentiation in the secondary lymphoid organs
- roles of IL-4 in differentiation of B and Th2 cells
- roles of IL-7 in the development of lymphoid progenitor cells in the bone marrow
Explanation of clinical evidence
Explains severe atrophy of both primary and secondary lymphoid organs and absence of mature B cells
- does not explain the elevated numbers of T cells at the age of 8 weeks
What are the 3 functionally distinct types of T cell developed from a common progenitor in the thymus?
- gamma/delta T cells (not MHC restricted)
- alpha/beta CD4+ T cells (MHC 2 restricted)
- alpha/beta CD8+ T cells (MHC 1 restricted)
Subsequent phases in the thymus only concern _____
Alpha/beta T cells
Positive selection tests the ability of ______ to interact with ____ expressed in the thymus
Alpha/beta TCRs; self-MHC molecules
Negative selection eliminates cells whose ________
Receptors interact too strongly with self-peptide; self MHC complexes
Main difference between thymus and bone marrow
Bone marrow continuously turns of B cell repertoire during the person’s lifetime, while the thymus works principally during youth to accumulate a repertoire of T cells that can be used throughout life
* reflects magnitude of body’s investment in development of useful T cells and savings to be made by gradually shutting down the thymus *
