Basic Immunology. White Blood Cell Mononuclear Leukocyte - T Cell, B cell, Null (LGL) Granulocyte...

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