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Invariantn? lymfocyty (lidsk?). CellsMHC Ligands ReceptorsNK TCD1d a-Gal/Cer Va14(24)/Vb8(11) Non a-Gal/Cer Va3.2,Va8/Vb8Tissue gd CD1c, MICA lipids Vg2/Vd1Blood gd ? Prenyl pyrophosph
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1. gamma delta T bunky Pokroky v imunologii
Listopad 2005
Karel Drbal
2. Invariantní lymfocyty (lidské) Cells MHC Ligands Receptors
NK T CD1d a-Gal/Cer Va14(24)/Vb8(11)
Non a-Gal/Cer Va3.2,Va8/Vb8
Tissue gd CD1c, MICA lipids Vg2/Vd1
Blood gd ? Prenyl pyrophosphates, Vg9/Vd2
phosphorylated nucleotides
MAIT cells MR1 peptides? Va19(7.2)/Ja33
CD8aa IEL TL CD8aa ?
B1 B cells - TI-antigens (PC) IgM
MZ B cells - TI-antigens (broad) IgM
NK cells MHC class I Variable KIR, Ly49, CD94-NKG2D/DAP12
Fetal liver-derived hV?9Vd2 cells express T-cell receptors (TCRs) with canonical junctions, whereas adult peripheral blood lymphocyte (PBL)-derived V?9Vd2 cells express junctionally diverse TCR with conserved specificity for phosphoantigens. Not listed are human
Vd1 T cells, a prominent subset in the intestinal epithelium, which has been associated with recognition of various antigens, including CD1c and MHC class I (MIC). This is because of the apparent absence of canonical sequence motifs and the naive phenotype of most Vd1 T cells. Similarly, ?d T cells specific for the non-classical T10 and T22 MIC molecules are not listed because of the lack of recurrent junctional motifs within the few reactive TCRs analysed so far.Fetal liver-derived hV?9Vd2 cells express T-cell receptors (TCRs) with canonical junctions, whereas adult peripheral blood lymphocyte (PBL)-derived V?9Vd2 cells express junctionally diverse TCR with conserved specificity for phosphoantigens. Not listed are human
Vd1 T cells, a prominent subset in the intestinal epithelium, which has been associated with recognition of various antigens, including CD1c and MHC class I (MIC). This is because of the apparent absence of canonical sequence motifs and the naive phenotype of most Vd1 T cells. Similarly, ?d T cells specific for the non-classical T10 and T22 MIC molecules are not listed because of the lack of recurrent junctional motifs within the few reactive TCRs analysed so far.
3. Expression of an unique, conserved T cell receptor (TCR)
Specialized anatomical distribution
Characteristic cell phenotypes
A distinct pathway of developmental maturation
Unique antigen specificities
A broad spectrum of cell-cell interactions
A unique capacity to protect the host against specific pathogens
A nonredundant capacity to regulate the course and consequences of immune responses
Uniquely age-dependent activitiesan hypothesis.
Fast response Obecné vlastnosti gd T bunek
4. Preskupení TCR lokusu postupne: TCRD->TCRG->TCRB->TCRA
zacíná Dd2-Dd3->Dd2-Jd1->Vd-Jd1 (vyskytuje se té u jiných lymfocytu: B a NK bunek)
5. Preskupení TCR lokusu
6. gd TCR nomenklaturapotvrzeno HUGO Gene Nomenclature Committee dostupné na: http://imgt.cines.fr clovek (funkcní jen 2 variabilní TRGV regiony Vg2, Vg9)
7. gd TCR nomenklaturapotvrzeno HUGO Gene Nomenclature Committee dostupné na: http://imgt.cines.fr clovek (funkcní jen 2 variabilní TRDV regiony Vd1-Vg2, Vd2- Vg9)
8. gd TCR nomenklatura my (uitecné srovnání pro starí citace), nová terminologie té dostupná na:http://imgt.cines.fr
9. Vývoj diverzity invariantního gd TCR behem ontogeneze omezený výber variabilních segmentu TCR
zvyující se CDR3 variabilita behem ontogeneze (více u Vd1) fetální strevo Vd1 Vd2
Fetal liver-derived hV?9Vd2 cells express T-cell receptors (TCRs) with canonical junctions, whereas adult peripheral blood lymphocyte (PBL)-derived V?9Vd2 cells express junctionally diverse TCR with conserved specificity for phosphoantigens. Not listed are human
Vd1 T cells, a prominent subset in the intestinal epithelium, which has been associated with recognition of various antigens, including CD1c and MHC class I (MIC). This is because of the apparent absence of canonical sequence motifs and the naive phenotype of most Vd1 T cells. Similarly, ?d T cells specific for the non-classical T10 and T22 MIC molecules are not listed because of the lack of recurrent junctional motifs within the few reactive TCRs analysed so far.
Fetal liver-derived hV?9Vd2 cells express T-cell receptors (TCRs) with canonical junctions, whereas adult peripheral blood lymphocyte (PBL)-derived V?9Vd2 cells express junctionally diverse TCR with conserved specificity for phosphoantigens. Not listed are human
Vd1 T cells, a prominent subset in the intestinal epithelium, which has been associated with recognition of various antigens, including CD1c and MHC class I (MIC). This is because of the apparent absence of canonical sequence motifs and the naive phenotype of most Vd1 T cells. Similarly, ?d T cells specific for the non-classical T10 and T22 MIC molecules are not listed because of the lack of recurrent junctional motifs within the few reactive TCRs analysed so far.
10. CDR oblasti ab vs.gd TCR CDR1, 2 MHC specifita Ag specifita diverzita: invariabilní variabilnívazba: MHC ligand
CDR3 Ag specifita diverzita: variabilní invariabilní vazba: peptid MHC (TL) somatická hypermutace Ig té zvyuje variabilitu hlavne u CDR1 a 2somatická hypermutace Ig té zvyuje variabilitu hlavne u CDR1 a 2
11. Unikátní lokalizace gd T bunek druhove unikátní - clovek < hlodavci < prevýkavci, ptáci
residentní v tkáních - pomer ab:gd - 1:50 (periferie, uzliny) vs. 1:5 (strevo)
první obranná linie - ? cetnost v periferii (mukózní povrchy, kue)
omezená migrace - prímo do tkání souvislost s Ag-specifitou: nemusí probírat vzácné Ag v LN jako to delají konvencní ab T bunkysouvislost s Ag-specifitou: nemusí probírat vzácné Ag v LN jako to delají konvencní ab T bunky
12. Myí vývojové linie tkánove specifická ontogeneze ve vlnách intrathymový klasický vývoj:fetální kue: (Vg5Vd1) DETC -pouze u myi, mukóza: (Vg6)- monospecifické (invariantní) TCR dospelý lymfoidní orgány: (Vg1, Vg4, Vg2, Vg7)-vysoká diverzita TCR
extrathymový vývoj (dospelý): strevo (Vg7, Vg1)
CD8aa (IEL) gd T bunky -vysoká diverzita TCRplíce, epitelie: -nízká diverzita nebo monospecifické (invariantní) TCR ~ Vg5Vd1 DETC ?
odpoved na stres (heat-shock, transformace, infekce)
DETC = dendritic epidermal T cells
IEL=intrapithelial lymphocytes
Figure 7.21. The rearrangement of T-cell receptor ? and d genes in the mouse proceeds in waves of cells expressing different V? and Vd gene segments. At about 2 weeks of gestation, the C?1 locus is expressed with its closest V gene (V?5; also known as V?3). After a few days V?5-bearing cells decline (upper panel) and are replaced by cells expressing the next most proximal gene, V?6. Both these rearranged ? chains are expressed with the same rearranged d-chain gene, as shown in the lower panels, and there is little junctional diversity in either the V? or the Vd chain. As a consequence, most of the ?:d T cells produced in each of these early waves have the same specificity, although the antigen recognized in each case is not known. The V?5-bearing cells become established selectively in the epidermis, whereas the V?6-bearing cells become established in the epithelium of the reproductive tract. After birth, the a:ß T-cell lineage becomes dominant and, although ?:d T cells are still produced, they are a much more heterogeneous population, bearing receptors with a great deal of junctional diversity. DETC = dendritic epidermal T cells
IEL=intrapithelial lymphocytes
Figure 7.21. The rearrangement of T-cell receptor ? and d genes in the mouse proceeds in waves of cells expressing different V? and Vd gene segments. At about 2 weeks of gestation, the C?1 locus is expressed with its closest V gene (V?5; also known as V?3). After a few days V?5-bearing cells decline (upper panel) and are replaced by cells expressing the next most proximal gene, V?6. Both these rearranged ? chains are expressed with the same rearranged d-chain gene, as shown in the lower panels, and there is little junctional diversity in either the V? or the Vd chain. As a consequence, most of the ?:d T cells produced in each of these early waves have the same specificity, although the antigen recognized in each case is not known. The V?5-bearing cells become established selectively in the epidermis, whereas the V?6-bearing cells become established in the epithelium of the reproductive tract. After birth, the a:ß T-cell lineage becomes dominant and, although ?:d T cells are still produced, they are a much more heterogeneous population, bearing receptors with a great deal of junctional diversity.
13. Lidské vývojové linie - ontogeneze Vd1 (tkáne)
-vysoká diverzita TCR
Vd2Vg9 (hlavne krev, cirkulace)
-omezená diverzita TCR
-nejcasnejí maturovaná populace lymfocytu behem ontogeneze (do 1 roku)
odpoved na stres (heat-shock, transformace, infekce)
We also find distinct differences between the V1 and V2 subpopulations
of T cells. Although both V1 and V2 cells display
signs of early activation in neonates, V2 cells in particular
are activated very early, with the majority of V2 cells showing
evidence of prior activation in individuals before 1 year. This represents
the earliest immunological maturation of any lymphocyte
compartment in humans and most likely reflects the importance of
these cells in controlling pathology due to common environmental
challenges.
We also find distinct differences between the V1 and V2 subpopulations
of T cells. Although both V1 and V2 cells display
signs of early activation in neonates, V2 cells in particular
are activated very early, with the majority of V2 cells showing
evidence of prior activation in individuals before 1 year. This represents
the earliest immunological maturation of any lymphocyte
compartment in humans and most likely reflects the importance of
these cells in controlling pathology due to common environmental
challenges.
14. Vd1 a Vd2 ontogeneze Vg9 párování s Vd1 a Vd2 fenotyp Vd1 a Vd2
15. Vd2 subsety IL-2, IFNg & perforin - produkce maturovanými gdT bunkami
16. Vd2 subsety obdobné jako u ab T bunek naive (Vd2 TN): CD62L+ CD27+ CD45RA+ CD16-
central memory (Vd2 TCM): CD62L+ CD27+ CD45RA- CD16-
effector memory (Vd2 TEMh): CD62L- CD27- CD45RA- CD16-
term. diff. eff. memory (Vd2 TEMRA): CD62L- CD27- CD45RA+ CD16+ ADCC = antibody dependent cellular cytotoxicity = Ab opsonized target cell (tumor)
BrHPP = phospholigandADCC = antibody dependent cellular cytotoxicity = Ab opsonized target cell (tumor)
BrHPP = phospholigand
17. Thymus Thymový lalok
18. Thymový vývoj Fig. 1. Stage-specific interactions associated
with the T-cell development in the thymus.
The thymus is a structurally complex primary
lymphoid organ composed of stromal cells and
immigrant hemopoietic cells, which can be
broadly divided into two main anatomical
regions, the outer cortex and the inner medulla.
Hemopoietic stem cells enter the thymus via
blood vessels at the corticomedullary junction,
and under the influence of stromal cell
components, undergo a series of phenotypically
and functionally characterized developmental
stages. Through the early stages of T-cell
development within the cortex, the developing
thymocytes lose the ability to give rise to
various non-T-cell lineages and gradually
become committed to the T-cell lineage.
Following successful MHC: TCR interactions
between developing thymocytes and resident
stromal tissues, the developing thymocytes are
selected to undergo final maturation, which
occurs within the thymic medulla prior to
export to the peripheral T-cell pool as fully
functional self-tolerant T cells.
Fig. 1. Stage-specific interactions associated
with the T-cell development in the thymus.
The thymus is a structurally complex primary
lymphoid organ composed of stromal cells and
immigrant hemopoietic cells, which can be
broadly divided into two main anatomical
regions, the outer cortex and the inner medulla.
Hemopoietic stem cells enter the thymus via
blood vessels at the corticomedullary junction,
and under the influence of stromal cell
components, undergo a series of phenotypically
and functionally characterized developmental
stages. Through the early stages of T-cell
development within the cortex, the developing
thymocytes lose the ability to give rise to
various non-T-cell lineages and gradually
become committed to the T-cell lineage.
Following successful MHC: TCR interactions
between developing thymocytes and resident
stromal tissues, the developing thymocytes are
selected to undergo final maturation, which
occurs within the thymic medulla prior to
export to the peripheral T-cell pool as fully
functional self-tolerant T cells.
19. Thymový vývoj Figure 1 | Thymus structure and function. The thymus is broadly divided into two histologically defined regions, the cortex
and the medulla, each of which contains several different thymic epithelial cell (TEC) subtypes. In adults, T-cell precursors enter
the thymus at the corticomedullary junction, and then begin a highly ordered differentiation programme, which is linked
to migration through the thymic stroma. Different thymocyte subsets are therefore found in spatially restricted regions of the
thymus. The thymic cortex has been separated into four regions by Lind and colleagues8: region 1, the corticomedullary
junction, is the site of entry into the thymus and contains uncommitted progenitors, CD4CD8 double-negative 1 (DN1) cells;
in region 2, cells differentiate to the DN2 stage, undergo a proliferative clonal expansion, and lose B- and natural killer (NK)-cell
potential; T-cell lineage commitment and the onset of T-cell receptor (TCR) ß-chain rearrangement occurs in DN3 cells in region
3; and the transition from DN to CD4+CD8+ double-positive (DP) status occurs in region 4. DP cells then migrate back through
the cortex and, having differentiated into either CD4+ or CD8+ single-positive (SP) cells, into the medulla. Positive selection
occurs mainly in the cortex, and requires cortical TECs, whereas negative selection occurs mainly in the medulla, and is
mediated by medullary TECs and thymic dendritic cells (DCs). SP cells that have completed the differentiation programme
egress from the medulla to the periphery. CEC, cortical epithelial cell; MEC, medullary epithelial cell.
Figure 1 | Thymus structure and function. The thymus is broadly divided into two histologically defined regions, the cortex
and the medulla, each of which contains several different thymic epithelial cell (TEC) subtypes. In adults, T-cell precursors enter
the thymus at the corticomedullary junction, and then begin a highly ordered differentiation programme, which is linked
to migration through the thymic stroma. Different thymocyte subsets are therefore found in spatially restricted regions of the
thymus. The thymic cortex has been separated into four regions by Lind and colleagues8: region 1, the corticomedullary
junction, is the site of entry into the thymus and contains uncommitted progenitors, CD4CD8 double-negative 1 (DN1) cells;
in region 2, cells differentiate to the DN2 stage, undergo a proliferative clonal expansion, and lose B- and natural killer (NK)-cell
potential; T-cell lineage commitment and the onset of T-cell receptor (TCR) ß-chain rearrangement occurs in DN3 cells in region
3; and the transition from DN to CD4+CD8+ double-positive (DP) status occurs in region 4. DP cells then migrate back through
the cortex and, having differentiated into either CD4+ or CD8+ single-positive (SP) cells, into the medulla. Positive selection
occurs mainly in the cortex, and requires cortical TECs, whereas negative selection occurs mainly in the medulla, and is
mediated by medullary TECs and thymic dendritic cells (DCs). SP cells that have completed the differentiation programme
egress from the medulla to the periphery. CEC, cortical epithelial cell; MEC, medullary epithelial cell.
20. Thymový vývoj CTECkortikální thymické epiteliální bunky
MTEC - AIRE medulární thymické epiteliální bunky Figure 1 | Overall scheme of T-cell development in the thymus. Committed lymphoid progenitors arise in the bone marrow and
migrate to the thymus. Early committed T cells lack expression of T-cell receptor (TCR), CD4 and CD8, and are termed double-negative
(DN; no CD4 or CD8) thymocytes. DN thymocytes can be further subdivided into four stages of differentiation (DN1, CD44+CD25-; DN2,
CD44+CD25+; DN3, CD44-CD25+; and DN4, CD44-CD25-)41. As cells progress through the DN2 to DN4 stages, they express the pre-
TCR, which is composed of the non-rearranging pre-Ta chain and a rearranged TCR ß-chain43. Successful pre-TCR expression leads
to substantial cell proliferation during the DN4 to double positive (DP) transition and replacement of the pre-TCR a-chain with a newly
rearranged TCR a-chain, which yields a complete aß TCR. The aß-TCR+CD4+CD8+ (DP) thymocytes then interact with cortical epithelial
cells that express a high density of MHC class I and class II molecules associated with self-peptides. The fate of the DP thymocytes
depends on signalling that is mediated by interaction of the TCR with these self-peptideMHC ligands6,51. Too little signalling results in
delayed apoptosis (death by neglect). Too much signalling can promote acute apoptosis (negative selection); this is most common in the
medulla on encounter with strongly activating self-ligands on haematopoietic cells, particularly dendritic cells123. The appropriate,
intermediate level of TCR signalling initiates effective maturation (positive selection). Thymocytes that express TCRs that bind selfpeptide
MHC-class-I complexes become CD8+ T cells, whereas those that express TCRs that bind self-peptideMHC-class-II ligands
become CD4+ T cells; these cells are then ready for export from the medulla to peripheral lymphoid sites. SP, single positive
Figure 1 | Overall scheme of T-cell development in the thymus. Committed lymphoid progenitors arise in the bone marrow and
migrate to the thymus. Early committed T cells lack expression of T-cell receptor (TCR), CD4 and CD8, and are termed double-negative
(DN; no CD4 or CD8) thymocytes. DN thymocytes can be further subdivided into four stages of differentiation (DN1, CD44+CD25-; DN2,
CD44+CD25+; DN3, CD44-CD25+; and DN4, CD44-CD25-)41. As cells progress through the DN2 to DN4 stages, they express the pre-
TCR, which is composed of the non-rearranging pre-Ta chain and a rearranged TCR ß-chain43. Successful pre-TCR expression leads
to substantial cell proliferation during the DN4 to double positive (DP) transition and replacement of the pre-TCR a-chain with a newly
rearranged TCR a-chain, which yields a complete aß TCR. The aß-TCR+CD4+CD8+ (DP) thymocytes then interact with cortical epithelial
cells that express a high density of MHC class I and class II molecules associated with self-peptides. The fate of the DP thymocytes
depends on signalling that is mediated by interaction of the TCR with these self-peptideMHC ligands6,51. Too little signalling results in
delayed apoptosis (death by neglect). Too much signalling can promote acute apoptosis (negative selection); this is most common in the
medulla on encounter with strongly activating self-ligands on haematopoietic cells, particularly dendritic cells123. The appropriate,
intermediate level of TCR signalling initiates effective maturation (positive selection). Thymocytes that express TCRs that bind selfpeptide
MHC-class-I complexes become CD8+ T cells, whereas those that express TCRs that bind self-peptideMHC-class-II ligands
become CD4+ T cells; these cells are then ready for export from the medulla to peripheral lymphoid sites. SP, single positive
21. Vývojová stadia * ISP in mouse express CD8, but in human express CD4
22. gd T vs. ab T-lineage commitment most probable competitive model: delta, gamma, beta simultaneous rearrangement which is productive dictates cell fate (but no direct evidence for this)
Figure 1. TCR Signal Strength and the aß versus ?d T Cell Fate
Decision
Early thymocyte precursors (CD4-CD8-, double negative, or DN)
rearrange their TCR ß, ?, and d genes and, depending on the outcome of rearrangement, may express either a ?dTCR (top) or a pre-TCR composed of ß TCR and an invariant preTa chain (middle).
Expression of a ?dTCR leads to a strong TCR signal, high levels of
ERK phosphorylation, strong induction of the Egr family of transcription factors, and ultimately promotes the ?d T cell fate. Expression
of the pre-TCR leads to a weaker TCR signal, moderate phosphorylation of ERK and Egr induction, and ultimately promotes the
aß T cell fate. Experimental manipulations that reduce ?dTCR signaling in the thymus (bottom, indicated by an x) promote the aß
fate at the expense of ?d development.
Figure 7. Signal Strength Model for aß/?d Lineage Choice
Immature DN thymocytes have the potential to become either an
aß or a ?d lineage cell, depending on the strength of the TCR signal.
The surface level of the TCR (pre- or ?dTCR) on immature DN thy-
mocytes determines its signal strength. Typically, the pre-TCR is
expressed at low levels on immature DN thymocytes, whereas surface
expression of the ?dTCR is relatively high. Therefore, if a cell
expresses the pre-TCR, then it will receive a weak signal, choose
the aß lineage fate, undergo a strong proliferative burst and transi-
tion to the DP stage. However, if a cell expresses high levels of the ?dTCR,
then it will receive a strong signal, choose the ?d lineage fate
and remain DN. Conversely, if it expresses low levels of the
?dTCR, then it will receive a weak signal and choose the aß lin-
eage fate. Because the choice to become an aß lineage cell by a
?dTCR+ DN thymocyte occurs infrequently in wild-type mice, it is
denoted by a dotted line.
most probable competitive model: delta, gamma, beta simultaneous rearrangement which is productive dictates cell fate (but no direct evidence for this)
Figure 1. TCR Signal Strength and the aß versus ?d T Cell Fate
Decision
Early thymocyte precursors (CD4-CD8-, double negative, or DN)
rearrange their TCR ß, ?, and d genes and, depending on the outcome of rearrangement, may express either a ?dTCR (top) or a pre-TCR composed of ß TCR and an invariant preTa chain (middle).
Expression of a ?dTCR leads to a strong TCR signal, high levels of
ERK phosphorylation, strong induction of the Egr family of transcription factors, and ultimately promotes the ?d T cell fate. Expression
of the pre-TCR leads to a weaker TCR signal, moderate phosphorylation of ERK and Egr induction, and ultimately promotes the
aß T cell fate. Experimental manipulations that reduce ?dTCR signaling in the thymus (bottom, indicated by an x) promote the aß
fate at the expense of ?d development.
Figure 7. Signal Strength Model for aß/?d Lineage Choice
Immature DN thymocytes have the potential to become either an
aß or a ?d lineage cell, depending on the strength of the TCR signal.
The surface level of the TCR (pre- or ?dTCR) on immature DN thy-
mocytes determines its signal strength. Typically, the pre-TCR is
expressed at low levels on immature DN thymocytes, whereas surface
expression of the ?dTCR is relatively high. Therefore, if a cell
expresses the pre-TCR, then it will receive a weak signal, choose
the aß lineage fate, undergo a strong proliferative burst and transi-
tion to the DP stage. However, if a cell expresses high levels of the ?dTCR,
then it will receive a strong signal, choose the ?d lineage fate
and remain DN. Conversely, if it expresses low levels of the
?dTCR, then it will receive a weak signal and choose the aß lin-
eage fate. Because the choice to become an aß lineage cell by a
?dTCR+ DN thymocyte occurs infrequently in wild-type mice, it is
denoted by a dotted line.
23. T- bunecné signální dráhy Figure 1. TCR Signal Strength and the aß versus ?d T Cell Fate
Decision
Early thymocyte precursors (CD4-CD8-, double negative, or DN)
rearrange their TCR ß, ?, and d genes and, depending on the outcome of rearrangement, may express either a ?dTCR (top) or a pre-TCR composed of ß TCR and an invariant preTa chain (middle).
Expression of a ?dTCR leads to a strong TCR signal, high levels of
ERK phosphorylation, strong induction of the Egr family of transcription factors, and ultimately promotes the ?d T cell fate. Expression
of the pre-TCR leads to a weaker TCR signal, moderate phosphorylation of ERK and Egr induction, and ultimately promotes the
aß T cell fate. Experimental manipulations that reduce ?dTCR signaling in the thymus (bottom, indicated by an x) promote the aß
fate at the expense of ?d development.
Figure 7. Signal Strength Model for aß/?d Lineage Choice
Immature DN thymocytes have the potential to become either an
aß or a ?d lineage cell, depending on the strength of the TCR signal.
The surface level of the TCR (pre- or ?dTCR) on immature DN thy-
mocytes determines its signal strength. Typically, the pre-TCR is
expressed at low levels on immature DN thymocytes, whereas surface
expression of the ?dTCR is relatively high. Therefore, if a cell
expresses the pre-TCR, then it will receive a weak signal, choose
the aß lineage fate, undergo a strong proliferative burst and transi-
tion to the DP stage. However, if a cell expresses high levels of the ?dTCR,
then it will receive a strong signal, choose the ?d lineage fate
and remain DN. Conversely, if it expresses low levels of the
?dTCR, then it will receive a weak signal and choose the aß lin-
eage fate. Because the choice to become an aß lineage cell by a
?dTCR+ DN thymocyte occurs infrequently in wild-type mice, it is
denoted by a dotted line.
Figure 1. TCR Signal Strength and the aß versus ?d T Cell Fate
Decision
Early thymocyte precursors (CD4-CD8-, double negative, or DN)
rearrange their TCR ß, ?, and d genes and, depending on the outcome of rearrangement, may express either a ?dTCR (top) or a pre-TCR composed of ß TCR and an invariant preTa chain (middle).
Expression of a ?dTCR leads to a strong TCR signal, high levels of
ERK phosphorylation, strong induction of the Egr family of transcription factors, and ultimately promotes the ?d T cell fate. Expression
of the pre-TCR leads to a weaker TCR signal, moderate phosphorylation of ERK and Egr induction, and ultimately promotes the
aß T cell fate. Experimental manipulations that reduce ?dTCR signaling in the thymus (bottom, indicated by an x) promote the aß
fate at the expense of ?d development.
Figure 7. Signal Strength Model for aß/?d Lineage Choice
Immature DN thymocytes have the potential to become either an
aß or a ?d lineage cell, depending on the strength of the TCR signal.
The surface level of the TCR (pre- or ?dTCR) on immature DN thy-
mocytes determines its signal strength. Typically, the pre-TCR is
expressed at low levels on immature DN thymocytes, whereas surface
expression of the ?dTCR is relatively high. Therefore, if a cell
expresses the pre-TCR, then it will receive a weak signal, choose
the aß lineage fate, undergo a strong proliferative burst and transi-
tion to the DP stage. However, if a cell expresses high levels of the ?dTCR,
then it will receive a strong signal, choose the ?d lineage fate
and remain DN. Conversely, if it expresses low levels of the
?dTCR, then it will receive a weak signal and choose the aß lin-
eage fate. Because the choice to become an aß lineage cell by a
?dTCR+ DN thymocyte occurs infrequently in wild-type mice, it is
denoted by a dotted line.
24. Interakce T bunek a thymového epitelu Dalí ligandy/receptory -> signální dráhy -> TF zodpovedné za lineage commitment T bunek a vývoj thymového epitelu:
Delta, Jagged / Notch
Wnt / Frizzled -> b-catenin -> TCF, LEF
FGF / FGFR -> Ras, MAPK -> Jun, Fos, STATs, Gli
TGFb, activins, BMPs / TGFR -> Smads
Sonic hedgehog / Patched, Smoothened ->Gli
(vetinou morfogenetické proteiny/dráhy) Figure 1. TCR Signal Strength and the aß versus ?d T Cell Fate
Decision
Early thymocyte precursors (CD4-CD8-, double negative, or DN)
rearrange their TCR ß, ?, and d genes and, depending on the outcome of rearrangement, may express either a ?dTCR (top) or a pre-TCR composed of ß TCR and an invariant preTa chain (middle).
Expression of a ?dTCR leads to a strong TCR signal, high levels of
ERK phosphorylation, strong induction of the Egr family of transcription factors, and ultimately promotes the ?d T cell fate. Expression
of the pre-TCR leads to a weaker TCR signal, moderate phosphorylation of ERK and Egr induction, and ultimately promotes the
aß T cell fate. Experimental manipulations that reduce ?dTCR signaling in the thymus (bottom, indicated by an x) promote the aß
fate at the expense of ?d development.
Figure 7. Signal Strength Model for aß/?d Lineage Choice
Immature DN thymocytes have the potential to become either an
aß or a ?d lineage cell, depending on the strength of the TCR signal.
The surface level of the TCR (pre- or ?dTCR) on immature DN thy-
mocytes determines its signal strength. Typically, the pre-TCR is
expressed at low levels on immature DN thymocytes, whereas surface
expression of the ?dTCR is relatively high. Therefore, if a cell
expresses the pre-TCR, then it will receive a weak signal, choose
the aß lineage fate, undergo a strong proliferative burst and transi-
tion to the DP stage. However, if a cell expresses high levels of the ?dTCR,
then it will receive a strong signal, choose the ?d lineage fate
and remain DN. Conversely, if it expresses low levels of the
?dTCR, then it will receive a weak signal and choose the aß lin-
eage fate. Because the choice to become an aß lineage cell by a
?dTCR+ DN thymocyte occurs infrequently in wild-type mice, it is
denoted by a dotted line.
Figure 1. TCR Signal Strength and the aß versus ?d T Cell Fate
Decision
Early thymocyte precursors (CD4-CD8-, double negative, or DN)
rearrange their TCR ß, ?, and d genes and, depending on the outcome of rearrangement, may express either a ?dTCR (top) or a pre-TCR composed of ß TCR and an invariant preTa chain (middle).
Expression of a ?dTCR leads to a strong TCR signal, high levels of
ERK phosphorylation, strong induction of the Egr family of transcription factors, and ultimately promotes the ?d T cell fate. Expression
of the pre-TCR leads to a weaker TCR signal, moderate phosphorylation of ERK and Egr induction, and ultimately promotes the
aß T cell fate. Experimental manipulations that reduce ?dTCR signaling in the thymus (bottom, indicated by an x) promote the aß
fate at the expense of ?d development.
Figure 7. Signal Strength Model for aß/?d Lineage Choice
Immature DN thymocytes have the potential to become either an
aß or a ?d lineage cell, depending on the strength of the TCR signal.
The surface level of the TCR (pre- or ?dTCR) on immature DN thy-
mocytes determines its signal strength. Typically, the pre-TCR is
expressed at low levels on immature DN thymocytes, whereas surface
expression of the ?dTCR is relatively high. Therefore, if a cell
expresses the pre-TCR, then it will receive a weak signal, choose
the aß lineage fate, undergo a strong proliferative burst and transi-
tion to the DP stage. However, if a cell expresses high levels of the ?dTCR,
then it will receive a strong signal, choose the ?d lineage fate
and remain DN. Conversely, if it expresses low levels of the
?dTCR, then it will receive a weak signal and choose the aß lin-
eage fate. Because the choice to become an aß lineage cell by a
?dTCR+ DN thymocyte occurs infrequently in wild-type mice, it is
denoted by a dotted line.
25. gd TCR ligandy obecné a konzervované struktury, indukované bunecným stresem ci transformací, casto self-Ag
Vd2 specifické
nepeptidové intermediát biosyntézy isoprenoidu:
bakteriální 1-deoxy-D-xylulose 5-phosphate (eubacteria, algae, plants, Apicomplexa) endogenní metabolity mevalonátové dráhy (eukaryotes, archaebacteria, and certain eubacteria)
pyrofosfomonoestery (alkylaminy a aminobisfosfonáty blokují mevalonátovou dráhu a tím zpusobují akumulaci pyrofosfomonoesteru, napr.: IPP - izopentenyl pyrofosfát)
(napr. HMB-PP, MEP)
nádory: Apolipoprotein A-I navázaný na F1-ATPázu
MICA: NKG2D zprostredkovaná stimulace Vd2 (pres NK receptor, nikoliv TCR)
Vd1 specifické
MHCIb bez peptidu, indukované stresem
lidské: MICA, MICB (chybí u myí): Vd1 stimulace
myí: T10/T22;(jiné ne MHCIb: MHC II, Hsp): Vg1, Vg2 stimulace
lipopeptidy, kys. mykolová (CD1a, b, c, e)
hydrofobní peptidy (N-formyl, signální peptidy) (MHC Ib)
26. gd T bunky: ochrana pred infekcí infekce virové (CMV, HIV) a spirochetové (Lymeská borelióza) -> Vd1 stimulace
infekce virové (EBV,chripka) a bakteriální (Mycobacteria sp., Listeria monocytogenes, Leishmania sp., Salmonella sp.) a protozoální (Plasmodium, Toxoplasma) -> Vd2 stimulace
27. gd T bunky: ochrana pred infekcí
28. gd T bunky: ochrana pred infekcí HIV
29. Imunoregulacní funkce cytolýza (bunecné interakce), cytokiny, chemokiny
pro- / proti-zánetlivá reakce (Vg4 vs. Vg1, Vg5 DETC) :
vetinou protizánetlivý úcinek, suprese
vývoj spontánní dermatitidy u gdTCR KO myizávislé na genetickém pozadí a prostredí
Ig class-switch, vývoj GC
tissue repair (KGF)
maturace DC GC = germinal center
KGF = keratinocyte growth factorGC = germinal center
KGF = keratinocyte growth factor
30. Imunoregulacní funkce GC = germinal center
KGF = keratinocyte growth factorGC = germinal center
KGF = keratinocyte growth factor
31. gd T bunky: cytokiny Th1 i Th2 specifické cytokiny dle okolností a gd T subsetu -> (spíe Th1)
velmi rychlá odpoved
tvarování celkové i specifické imunitní odpovedi
32. gd T bunky jako APC Vg5Vd1 DETC (my) a Vg9Vd2 (clovek)
prezentace Ag ab T bunkám na CD1, MHCI? (cross-presentation)
prezentace Ag ab T bunkám na MHCII & kostimulace > profesionální APC
33. Journal Club Monost výberu vdy po 2 cláncích:
funkce gdTC jako APC
gd TCR struktura a vazba na TL (MHC Ib)
thymový vývoj gd TC a lineage commitment
http://www.img.cas.cz/mi/prednasky/