basic immunology. white blood cell mononuclear leukocyte - t cell, b cell, null (lgl) granulocyte...
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Basic Immunology
White Blood Cell
• Mononuclear Leukocyte - T Cell , B cell, Null (LGL) • Granulocyte – PMN Leukocyte
• NK cell
• Mono-Macrophage system
Immune system
• Innate Immunity Granulocyte – PMN Leukocyte NK cell Mono-Macrophage system
• Adaptive immunity APC T and B cell
Organization of normal lymphoid system
Thymus ?Bone marrow? Peyer patches
Lymph node, Spleen, Mucosal sites
CENTRAL COMPARTMENT: Reservoir for precursor cells; 'nursing' home for maturation
PERIPHERAL COMPARTMENT: Reservoir for mature cells, ready to respond to antigens
T B NK
?
Thymus
Thymus
• Site of T cell differentiation and maturation
• 구조 :
Lobule:
Cortex-Medulla
Thymus of a newborn
Hassall’s corpuscle
Thymic epithelium ( cytokeratin immunostain)
Lymphocytes
T lymphocyte (thymocyte)
• Medium sized immature thymocyte in subcapsular region and cortex
• Small lymphocytes in medulla
B lymphocytes• CD2+ CD40+
(subset)• Asteroid cell
: microenvironment of medulla
CD3 (pan-T)
CD20 (pan-B)
Other cells
• Myoid cell: acetylcholine receptor-like material on surface
• Macrophage: cortex and medulla
• Interdigitating dendritic cell: medulla, HLA-DR+
ProthymocyteSubcapsular thymocyte
Cortical thymocyte
Medullary thymocyte
Peripheral T cell
Precursor cells Mature T cells
Cytoplasmic SurfaceCD4
CD8
CD1
CD4, CD8
CD3CD2
CD7TdT
A Model for the Regulation of T Cell Fate by Notch and TCR Signals
Cell, 1997, 88;6:833-843
DiGeorge syndrome
In the mid 1960s, Angelo DiGeorge, MD, an endocrinologist
A genetic disorder
Clinical features • Hypoparathyroidism (underactive parathyroid gland), which results in hypocalcemia (low blood calcium levels) • Cypoplastic (underdeveloped) thymus or absent thymus, which results in problems in the immune system • Conotruncal heart defects (e.g., tetralogy of Fallot, interrupted aortic arch, ventricular septal defects, vascular rings)
• Cleft lip and/or palate
Markert, M. L. et al. Transplantation of thymus tissue in complete DiGeorge syndrome. N. Engl. J. Med. 341, 1180–1189 (1999).
Treatment
This paper shows that the transplantation of thymi of
young children into patients suffering from complete
DiGeorge syndrome results in the appearance of
mature T cells.
This not only describes a much-needed therapeutic
intervention for these patients, but also conclusively
shows the essential role of the thymus for T-cell
development in humans
Thymic epitherial cell : Donor origin
Thymocyte : recipient origin
Miller, J. F. A. P. Immunological function of the thymus. Lancet 2, 748–749 (1961).
However,
The basic principle of thymic dependency of T-cell production had been established in the mouse more than 40 years earlier
The thymus is critical for the maturation of bone marrow derived cells into T cells
Defect in antigen-receptor gene rearrangement
Defect in the thymus
How many T cells are alive and leave the thymus
• 108 to 2X108 cells in the thymus (in the case of mouse)
• About 5X107 new cells are generated each day
• 106 to 2X106 cells leave the thymus (~2-4%)
• Despite the disparity, the thymus does not continue to grow in size or cell number
• ~98% thymocytes die within the thymus (by apoptosis rather than by necrosis)
Red: apoptotic cellsBlue: macrophage
• Progenitor T cells from sites of hematopoiesis begin to migrate to thymus at about 11 days of gestation in mice and in the eight or ninth week in humans.• T cell maturation similar to B cells involves rearrangements of the germ-line TCR genes and expression of various membrane markers;• Developing T cells in the thymus are known as thymocytes.• Thymocytes proliferate and differentiate into distinct subpopulations of mature T cells ;.• The antigenic diversity of T cells is reduced during maturation in the thymus by a selection process that allows only MHC-restricted and nonself-reactive T cells to mature ;• T cells selection processes include positive and negative selection in the thymus.• Finally functionally distinct mature CD4+ and CD8+ subpopulations that exhibit class II and class I MHC restriction respectively exit thymus.
T cell Maturation & Development-1
If injected into the peripheral circulation,can even give rise to B cells and NK cells
CD2 or Thy-1 molecules : the first cell-surface molecules specific for T cells
DN
DP
SP
T cell development take place in the cortex and medullar
TCR gene rearrangement in the thymus
D/J rearrangement
V/DJ rearrangement
/pTCD3 complex:- Triggers pho-and degradation of RAG-2- Halting -chain gene rearrangement (allelic exclusion)
TCR /CD3 complex:
DN
DP
Schematic representation of the pT/TCR complex
Pre-T-cell receptor (pre-TCR) signalling
Positive and negative selection in the thymus
Positive selection
• After completion of TCRα rearrangements, αβ T cells die unless they
are rescued by a low-affinity interaction of the TCRαβ heterodimer with
self-peptides complexed with MHC antigens that are expressed on thymic
epithelial cells.
• Selection for Thymocytes with TCR’s capable of binding MHC (MHC
restriction)
Negative selection
• Thymocytes that express high-affinity receptors for self-peptide–MHC
expressed on thymic DCs are deleted in a process that is known as
negative selection
• Elimination of thymocytes that have TCR’s that have:
high affinity self MHC / bind self-MHC + self peptide (Self tolerance)
Selection of mature T cells from thymocytes
Where do thymocytes undergo negative selection?This has been controversial
Positive selection :MHC class I & lass IIexpressed on epithelial cells
Negative selection :Macrophage &Dendritic cells
Positive and negative selection in the thymus
T cell development in mouse thymus : Overview
Precursor
DN
DP
SP
Success rate (survival rate): <5%
T cell development in the human
Early stages of human T-cell development
• The thymus blood-borne precursor cells (originate from bone-marrow stem
cells)
• Cord-blood progenitor cells
CD34+cells
Lack expression of recombination-activating gene 1 (RAG1), and
CD1A,
cytoplasmic CD3 , CD2 and CD7
A common T/NK-cell progenitor (J. Exp. Med. 180, 569–576 (1994):
The first study to prove that T cells and NK cells are derived from a common
precursor)
Dendritic-cell (DC) precursors;
Plasmacytoid DCs (PDCs) precursors
• Thymic immigrants enter through the junction between the medulla and
cortex
• T-cell precursors migrate outwards in the cortex and accumulate in the
subcapsular zone
• The transition of CD34+CD1A- cells to a CD34+CD1A+ stage is strongly
associated with T-cell commitment, because CD34+CD1A+ cells, in contrast to
CD34+CD1A- precursors, have strong T-cell, but little NK-cell and no DC or
PDC,
precursor activity
• Cell-fate determination of lymphoid lineages at early stagesE proteins
a subfamily of basic helix–loop–helix transcription factorsthe inhibitor of DNA binding (ID) proteins
ID Proteins Determine the lineage choice between T cells, B cells and
PDCs • NOTCH1 A factor that determines the choice between T- and B-cell fate
(Immunity 10, 547–558 (1999).)
CD1a marks commitment to the T cell lineage
CD4ISP
CD4
Positive & negative selection