9- Development of T Lymphocytes Flashcards
Why does a thymectomy after birth not cause immediate immune deficiency?
Mature T cells leave the thymus and colonize peripheral lymphoid organs by the 14th week, so by the time the baby is born they peripheral T-cell repertoire has been established.
DiGeorge Syndrome
Aka velo-cardio-facial syndrome (VCSF).
Caused by a large deletion in chromosome 22 which leads t the absence of a functional thymus.
Causes complete T cell deficiency, severe immunodeficiency, history of heart defects and characteristic facial features.
FOXN1 mutation
Mutation in gene which encodes a transcription factor that is essential for the functional maturation of thymic epithelial cell progenitors.
The immature epithelial cells fail to recruit HSC’s into the organ so none of the thymic dependent subsets (CD4+, CD8+, NKT, or Treg) are formed.
TEC
Thymic Epithelial Cells
Provide 3 functions for T-cell development:
- Production of cytokines IL1, 6, 7, stem cell factor, and thymic stroma lymphopoietin (TSLP)
- Expresses cell surface molecules such as DL-4 and DL-1 for the notch receptors. Required for T cell lineage commitment.
- Expresses MHC clases I/II and self antigen complex, which controls the selection of maturing T cells.
Thymocytes
Predominant lymphoid cells in the thymus, Derived from the hematopoietic stem cells, and after arriving in the thymus, these bone marrow HSC’s progress through tightly regulated steps to develop into mature T cells.
Surface marker of HSC
CD34
4 developmental events in T cells
- T lineage commitment
- Proliferation and Differentiation
- Selection: positive/ negative
- Maturation
T Lineage Commitment
HSC has a Notch receptor.
Interaction of Notch receptor with the Delta-Like 1 or 4 (DL-1/DL-4) induces T lineage commitment and terminates other lineage options.
Once committed cell expresses CD1A and begins to rearrange TCR Gamma, Delta and Beta genes.
IL-7 is also needed for this developmental stage.
Where does negative selection of T cells normally occur?
Predominantly in the cortical-medullary region, where a high density of thymic Dendritic Cells are present. The DC’s are responsible for phagocytosis of the apoptotic cells.
AIRE
What are the diseases which occur with mutations in AIRE?
Auto Immune Regulator Element
A gene which encodes a transcription factor that induces expression of a number of the antigens which are normally found in peripheral tissues. This induces negative selection and contributes to the prevention of organ specific autoimmunity by killing cells which recognize organ antigens.
Diseases: APECED or APS1
TCR gamma-delta cells
- present at a low level (1-5% of alpha-beta)
- predominantly CD4/CD8 NEGATIVE
- Direct antigen biding (no MHC I or II)
- Narrow repertoire
2 TYPES:
1.) cells that express delta-1 w/ various gamma genes –> LYSE STRESSED/TRANSFORMED EPITHELIAL CELLS
2.) TCR gamma-9 delta-2: majority of circulatory gamma-delta T-cells. –> recognize non-peptide antigens, TB, and produce IFN-gamma.
IFN-gamma
Affects cytotoxicity of NK and NKT cells and the generation of TH1 cells.
NKT cell function and basic development
FUNCTION: Rapidly produce Th1 and Th2 cytokines upon triggering. Thus play role in immunoregulation.
DEVELOPMENT: Develop in thymus from double positive thymocytes. DP that recognize glycolipid antigens presented by CD1D+ Thymocytes, develop to NKT cells. NKT cells are either CD4 positive, or double negative.
Express both the NK marker CD56+ and the Tcell marker T-alpha/beta CD3+
Treg
A Thymus generated CD4+ CD25+ suppressor cell with specificity for autoreactive T cells that may escape negative selection during the development of T cells.
Referred to as DOMINANT TOLERANCE, in contrast to the central tolerance in which the autoreactive T cells were deleted.
Treg development in the periphery
Treg can be generated from peripheral mature CD4+ T cells via TGF-B
