T cell development of T lymphocytes
Developmental pathways T and B lymphocytes have much in
common:
• Derive from bone marrow stem cells
• Use somatic recombination
• Use somatic hypermutation
T cells originate from bone marrow stem cells, migrate to mature in
thymus (thymus-dependent lymphocytes (T cells)). Thymus is primary
lymphoid organ and not involved in lymphocyte recirculation, only
enter and leave from the blood. Progenitor cells give rise to thymocytes
and dendritic cells. T cell progenitors enter thymus at junction between
cortex and medulla. Thymocytes move through cortex outward to
subcapsular region, move back from outer cortex to inner cortex and
medulla. Complete DiGeorge syndrome: thymus does not develop and
T cell are absent, B cells are made. Involution of the thymus:
development before birth, after 1 year starts to degenerate with fat
replacing thymocytes. Mature T cells are long-lived, self-renewing or
both. B-cells are short-lived and need constant replenishment from
bone marrow.
Interacting with thymic stroma, progenitor cells are signaled to divide,
proliferate and differentiate. After a week, lost all stem-cell markers,
become committed thymocytes of T cell lineage, expression CD2. Double-
negative thymocytes don’t express CD4 or CD8. Cytokine IL-7 crucial for T
cell development, secreted by thymic stromal cells and binds to IL-7
receptor on CD34 progenitor cells. Notch1, thymocyte cell-surface receptor
interacts with transmembrane protein ligands on thymic epithelial cells.
Notch1 keeps thymocytes on the pathway of T cell differentiation (like Pax-
5 in B-cell development). Extracellular Notch1 binds Notch ligand →
releases Notch1 intracellular → migrate to thymocyte nucleus →
transcription-factor complex needed for T cell development.
αβ and γδ T cells derive from common double-negative thymocyte
precursor. About same time, rearrangement γ, δ, and β loci (race to
make productive gene rearrangements and functional T-cell
receptor chains. Functional γδ receptor before β chain → becomes
γδ T cells. β chain first → pre-T-cell receptor. Gene rearrangements
stops, proliferates and expresses CD4 and CD8 co-receptors
(double-positive thymocytes). Rearrangement α chain, but also γ
and δ chain genes (still going on). Makes αβ receptor before γδ
receptor, commits αβ lineage. Fail productive T cell receptor → die
by apoptosis and phagocytes by macrophages thymic cortex.
β chain and δ chain, V, D and J segments, first rearrangement D and
J, later DJ with V. α chain and γ chain, V and J segments, V joins J.
γδ receptor to cell-surface, halt signal to rearrangement β chain.
They enter the circulation via blood. More frequent is productive β
chain before rearrangement of γδ.
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,β chain translocated to ER, test
capacity binding pTα (surrogate
α chain). If they bind, two heterodimers will form
superdimer, pTα makes contact with C and V regions β
chain. Each heterodimer of superdimer assembles with
CD3 complex and the ζ chain to form functional pre-T
cells receptor. Successful passes checkpoint pre-T cell
receptor (CD3 and Lck) becomes pre-T cell. β chain fails
assemble pre-T cell receptor, die by apoptosis. First and
non-productive rearrangement β chain can be followed
by second productive rearrangement of β chain.
Rearrangement of α chain gene occurs only in pre-T cells.
Pre-T cell receptor, halt gene rearrangements causing
degradation of the proteins of RAG complex. Pre-T cell
signaled to proliferate, creates clone of cells expressing
same β chain, accompanied by expression first CD8 and
then CD8 (expressing both) (inner cortex). Repeated α
chain rearrangements are possible. δ locus situated
within α chain, δ locus deleted. Productive α chain binds
to β chain and assemble T-cell receptor (second
checkpoint). Binding not successful → die by apoptosis.
Signals coming from the pre-T cell receptor depend on
the presence of CD4, CD8, CD3 signaling complex,
tyrosine kinase ZAP70 and Lck. Cd2 is adhesion molecule
interacts with CD58 on other cells.
T cells that recognize self-MHC molecules (with self-
peptides) undergo positive selection in the thymus. If not,
they die by apoptosis. Positive selection takes place in
cortex of thymus. MHC restriction: T cell response
dependent on MHC molecule and pathogen-derived antigen
(peptide). Thymoproteasome: only cortical epithelial
thymus produces self-peptides, subunit β5t replaces β5i.
Continuing α chain rearrangement
increases the chance of positive selection.
If T-cell receptor doesn’t bind self-MHC
molecule, α chain gene rearrangement
continuous. Double-positive thymocytes
can express two different α chains and two
different T-cell receptors, increases change positive selection. Expression of both
CD4 and CD8 increases positive selection because they can either bind self-MHC
class I or self-MHC class II. Binding self-MHC class I contain CD8, CD4 and MHC class
II spread diffusely on their respective cell surfaces. For binding self-MHC class II it is
the other way around. Lck commit the cell to either CD4 or CD8 lineage. Now the
cells are single-positive thymocytes because they express either CD4 or CD8.
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,T cells specific for self-antigens (peptides) are
removed in the thymus by negative selection. T cells
binding too strongly to self-peptides (in self-MHC
molecules) are autoreactive and could cause
autoimmune disease. Most important cells for
negative selection are macrophages and dendritic
cells derived from the bone marrow. If the TCR binds
the self-peptide too strongly, die by apoptosis and
phagocytosed by macrophage.
Transcription factor autoimmune regulator (AIRE)
helps mature T cells to be tolerant of proteins made
by one or a few cell types not presented in the
thymus. Lacking AIRE gives autoimmune disease autoimmune
polyendrocrinopathy-candidiases-ectodermal dystrophy (APECED). One
mechanism to render self-reactive T cells anergic.
Regulatory T cells (Treg cells) have T-cell receptors that recognize self-antigen.
Expression of CD25 on cell-surface and unique transcriptional repressor protein
FoxP3. Contacting self-antigens, Treg suppress activation and proliferation of naïve
T cells responding to self-antigens.
T cells differentiate further after antigen recognition in secondary lymphoid tissue.
Naïve T cells are activated by their specific antigens, final fase → mature T cell
becomes effector T cell. CD8 T cells become activated cytotoxic T cells. CD4 T cells
become regulatory T cells or various types of helper cells (different cytokines).
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, T cell mediated immunity
Myeloid dendritic cells carry antigens from sites of infection to
secondary lymphoid tissues and present them to naive T cells. Blood
infections stimulate T cells in spleen, mucosal tissues infection
stimulate T cells closely associated secondary lymphoid tissue.
Dendritic cells in the skin are immature dendritic cells,
in lymph nodes are mature dendritic cells. On
maturation, the finger-liked processes become highly
elaborated, interaction with T cells in cortex of lymph
node. Macrophages are present in cortex and medulla of
lymph node and extract pathogens and their breakdown
products from lymph node preventing pathogens from
leaving in the efferent lymph (gaining access to the
blood) and causing life-threating systemic infections.
Dendritic cells are adept and versatile at processing
pathogen antigens. Naive CD8 T cells can only be
activated by DCs, naïve CD4 T cells can be activated by
DCs and macrophages. Receptor mediated endocytosis captures bacteria and virus
particles extracellular fluid and targets them to be processed in lysosomes.
Micropinocytosis: small volumes of extracellular fluid. Macropinocytosis: large volume of
extracellular fluid, capture pathogens not recognized by endocytic receptors. Pathogens
are processed into peptides and presented at cell-surface in MHC molecule. Toll-like
receptors are expressed by DCs leading to activation of DC (improve efficiency antigen
uptake). Activation → appearance CCR7 (receptor of CCL21) DC leaves lymph and enter
tissue of draining lymph node, drive to mature.
Naïve T cells first encounter antigen presented by DCs in secondary lymphoid tissue.
Within lymph node high endothelial venules (HEV) bringing T cells
in outmost part of cortex T-cell area/zone. Interaction with DCs
take place, TCR with MHC:peptide, retained in lymph node and
activated by DC. Alternative route naïve T cell enter lymph node in
the afferent lymph. Naïve T cells entered upstream lymph node,
didn’t encounter specific antigen, leave lymph node to
downstream lymph node and enter via afferent lymph. Enter T-cell
area directly looking for specific antigen.
Homing of naïve T cells to secondary lymphoid tissues is
determined by chemokines CCL21 and CCL19 (secreted by stromal
cells and DCs in T-cell area). CCL21 and CCL19 bind surface high
endothelial cells, naïve T cells express CCR7 binding CCL21 and
CCL19. Interaction of T cell with endothelial cells involve cell-
adhesion molecules:
• L-selectin on T cell surface binds CD34 and GlyCAM-1 on
endothelial cells (slow down naïve
T cell and attach high
endothelium).
• Integrin LFA-1 on T cells surface
binds adhesion molecules ICAM-1
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