chapter 7 - development of t-cell lymphocytes

test 3

t cells develop in the _____

thymus

t cell precursors travel from the ______ ______ to develop in the thymus. then, mature t cells leave the thymus and travel to ______ ______ ______.

bone marrow; secondary lymphoid tissues

cellular organization of the thymus

• consists of two symmetrical lobes each enclosed by capsule from which trabeculae extend, and divides each lobe into two lobules

• lobule consists of: cortex and medulla

• cortex contains: immature thymocytes, cortical epithelial cells and macrophages

• medulla contains: mature thymocytes, medullary epithelial cells, dendritic cells and macrophages

what kinds of cells form the thymic stroma and nurture developing thymocytes?

cortical epithelial cells

thymocyte

immature (developing) T cell found in the thymus

is the thymus fully developed at birth?

no, it is most active early after birth and degrades after puberty (involution); replaced with fat tissue

why does thymus degeneration or a thymectomy (removal of the thymus gland) have no distinct impact on t cell immunity?

because mature T cell repertoire is long-lived and self-renewing (the T cell repertoire is largely established during childhood and lasts for rest of lifetime)

DiGeorge Syndrome (Thymic Hypoplasia)

genetic disease where the thymus fails to develop → cannot develop T cell immunity

why is DiGeorge syndrome also called hyper-IgM syndrome?

individuals with DiGeorge syndrome often have normal or elevated levels of IgM but reduced levels of other Igs like IgG, IgA, and IgE due to a defect in T-cell development

which markers are active and which are inactive when an uncommitted progenitor cell becomes a double negative thymocyte committed to the T cell lineage?

how are genes required for T cell development activated?

• notch ligand in thymic epithelium binds to extracellular domain of Notch 1 receptor on thymocyte (plays same role as Pax-5 in B cells)

• binding sends signal to intracellular domain of Notch 1

• protease cleaves Notch 1 intracellular domain --> travels to nucleus

• in the nucleus, Notch 1 intracellular domain (and co-activator molecule) acts as a transcription factor → activates genes required for T cell development by removing repressor and co-repressor

a common double negative T cell progenitor gives rise to...

alpha:beta and gamma:delta T cells (know steps in process as shown on diagram)

what genetic rearrangements occur to form alpha:beta T cells and gamma:delta T cells?

what is the checkpoint for the beta chain in T cells?

heterodimer → superdimer → pre-T-cell receptor → T-cell receptor

• the superdimer initially stops all gene rearrangement, then allows for expression of CD4 and CD8, and then resumes rearrangement

rearrangements of the beta chain locus

two attempts can be made to achieve a productive rearrangement of the beta-chain locus (2 on each chromosome = 4 total) → increases chances of successful rearrangement (80% vs 50% in B cells)

rearrangements of the alpha chain locus

the alpha-chain locus can sustain many attempts at a functional rearrangement (again, much higher chances that successful gene rearrangement will take place)

what is distinct about the alpha-chain locus rearrangement in T cells?

both alpha-chain loci can be rearranged at the same time → can potentially results in 2 different alpha chains → can become 2 different TCRs on a single cell → does not affect the avidity because there is only a single binding site on the T cell

rearrangement of an alpha-chain gene always results in...

the elimination of the linked delta-chain locus (decreases chances of making a gamma:delta T cell even more)

list the specific surface molecules that correspond to the following in T cells:
1) signaling
2) IL-2 receptor
3) co-receptor
4) lymphoid-specific recombinase
5) N-nucleotide addition
6) surrogate alpha chain
7) signal transduction
8) transcription factor

1) signaling: Kit and Notch
2) IL-2 receptor: CD25
3) co-receptor: CD4 and CD8
4) lymphoid-specific recombinase: RAG-1 and RAG-2
5) N-nucleotide addition: TdT
6) surrogate alpha chain: PTalpha
7) signal transduction: ZAP-70, CD3, Lck, and CD2

8) transcription factor: Ikaros, GATA-3, and Th-Pok
(look at complete table on slide 15)

summary of the early development of alpha:beta T cells in the thymus

know steps of process shown on diagram

• enter through HEVs (high endothelial venules)

• immature double positive cells express CD4 and CD8

• mature double positive cells undergo a second round of development (selection process) following this

positive selection of T cells in the thymus

• takes places in the cortex of the thymus

• cortical epithelial cells express both MHC class I and II molecules

• moderate/strong binding of TCR to MHC molecule → cell lives

• weak/no binding of TCR to MHC molecule → cell dies

• only ~2% of developing T cells make it through positive selection

double positive to single positive T cells

the type of T cell that is produced depends on which type of MHC molecule the TCR binds to first (MHC I = CD8 and MHC II = CD4)

negative selection of T cells in the thymus

• ensures that developing T cells do not bind to "self" (central tolerance process)

• low/moderate binding of TCR to MHC molecules → cell lives

• tight binding of TCR to MHC molecules → cell dies

regulatory CD4 cells

• regulatory T cells (Treg) suppress autoreactive T cells

• requires them to interact with the same antigen-presenting cell

after encounter with an antigen, T cells undergo further differentiation in...

secondary lymphoid tissues

t cell differentiation in secondary lymphoid tissues

t cells enter through HEVs → localize in T cell area → undergo differentiation process to become CD4 helper cells or CD8 cytotoxic cells (look at diagram on slide 22)