Peripheral B and T cell differentiation - University Institute of ...

Cellular and Molecular Immunology
30 October 2008
Peripheral B and T cell differentiation
Christoph Mueller, Institute of Pathology
University of Bern
• General principles:
- functional subsets
- plasticity vs. stability of phenotype
• Molecular basis of lymphocyte differentiation:
transcription factors
• Soluble factors and cognate interactions involved in
the differentiation of lymphoid cells
• Experimental approaches to study B/T cell differentiation
• Consequences of impaired T and B cell differentiation

RAG-1, 2
• RAG1 and RAG2 (“Recombination Activation Genes”)
are essential for the rearrangement of the Ig and TCR
genes
• Mice deficient for either RAG1 and/or RAG2 are
deficient for both T and B cells (but may still have some
NK cells)
• to prevent the later generation of autoreactive T and B
cells, the expression of these two genes needs to be
tightly regulated

CD8 T cell differentiation

Functional Heterogeneity of
CD4 T Lymphocytes
naive CD4 T Cell
Th1 Th0 Th2
ThO: IL2, IL3, IL4, IL5, IL6, IL9, IL10, IFN
Th1: IL2, IFN , TNFlymphotoxin
Th2: IL4, IL5, IL6, IL9, IL10

Functional Heterogeneity
of CD4 T Lymphocytes
naïve CD4 T Cells
Th1 Th0 Th2
cellular
immunity
humoral
immunity

Functional Heterogeneity of CD4 T
Lymphocytes is Controlled by Different
Transcription Factors
naïve CD4 T Cells
Th1 Th0 Th2
T-bet
GATA-3

Naïve
CD4
IL 4
IL 12
IFN
Th 2 Th 1
Grogan & Locksley Curr Opinion Immunol 14: 366-72; 2002

JCI 109;:431;2002
Pathways thought to regulate
the development of Th2 cells

Leprosy
• Chronic - progressive infectious disease, affecting the
skin, peripheral nerves and occasionally the respiratory
tract
• Infectious agent: Mycobacterium leprae
• Globally, approx. 10-20 million patients infected,
endemic in tropical areas (e.g. Southeast Asia; India,
South America, Subsaharan Africa)

Leprosy:
different clinical forms of the disease
Lepromatous Leprosy:
• Multiple, nodular lesions of the skin, in particular, of the
face (”lion face").
• Persistent bacteriemia, foamy cell-like lesions with
numerous M. leprae present
Tuberculoid Leprosy:
• Singular, small macular lesions of the skin.
• Peripheral nerves (e.g. N. ulnaris, peronealis, N.
auricularis) are often affected sensory neuropathy.
• Granuloma are frequent (with only low numbers of
M. leprae present)

Immunological Spectrum of Leprosy
naïve CD4 T cells
Th1 Th0 Th2
cellular
immunity
humoral
immunity
Tuberculoid leprosy
Granuloma formation
Tissue damage may ensue
Lepromatous leprosy
Persistence of M. leprae
Disfiguring disorder

Type IV Hypersensitivity reactions
Fig. 5-11
Kumar 6th edition

Pathogens may influence the resulting adaptive immune response
Science 302: 993-4; 2003

Figure 1 Stimulating the Th1 or Th2 response. In both pathways, dendritic cells internalize the
pathogen. They present its antigens to T cells, which recognize antigens through their T-cell receptors
(TCR). a, Organisms such as intracellular bacteria or viruses are recognized by the Toll-like
receptors on dendritic cells; the resulting signals induce the secretion of interleukin-12 (IL-12) and
differentiation of CD4 T cells into the Th1 lineage that produces gamma interferon (IFN-). b, How
dendritic cells recognize larger pathogens, such as parasitic worms, is not known. But the end result
is differentiation of Th2 effector cells regulated by T-cell-produced interleukin-4 (IL-4).
Information1, 2 on the link between dendritic cells and T cells suggests that the former express
different Notch ligands — Delta or Jagged — under different conditions. Jagged is specifically
induced by stimuli known to induce Th2 differentiation. Notch signals (Notch-IC) can induce
transcription of IL-4 through direct binding of RBPJ to the IL-4 promoter1
Nature 430, 150 - 151 (08 July 2004)

# Publications per Year (PubMed)
Publications on Suppressor T cells and
Regulatory T cells
300
250
200
Suppressor T cells
Regulatory T cells
150
100
50
0

Rregulatory T cell subsets
Natural regulatory T cells express the cell-surface marker CD25 and the
transcriptional repressor FOXP3 (forkhead box P3). These cells mature and migrate
from the thymus and constitute 5–10% of peripheral T cells in normal mice. Other
populations of antigen-specific regulatory T cells can be induced from naive
CD4 + CD25 - or CD8 + CD25 - T cells in the periphery under the influence of semimature
dendritic cells, interleukin-10 (IL-10), transforming growth factor- (TGF-) and
possibly interferon- (IFN-). The inducible populations of regulatory T cells include
distinct subtypes of CD4 + T cell: T regulatory 1 (T R 1) cells, which secrete high levels
of IL-10, no IL-4 and no or low levels of IFN-; and T helper 3 (T H 3) cells, which
secrete high levels of TGF-. Although CD8 + T cells are normally associated with
cytotoxic T-lymphocyte function and IFN- production, these cells or a subtype of
these cells can secrete IL-10 and have been called CD8 + regulatory T cells.

IFN-mediated STAT1 signaling leads to the induction of T-bet and
differentiation of T H 1 cells. IFN- production is further potentiated by
inflammatory cytokines such as IL-6. TGFß- induces Foxp3 expression in naive
CD4 + T cells and their differentiation into induced T reg cells. IL-6 is a potent
inhibitor of TGFß--induced Foxp3 induction in CD4 + T cells. However,
stimulation with both TGFß- and IL-6 results in the expression of RORt and
subsequent differentiation of T H -17 cells.

Natural regulatory T cells express the cell-surface marker CD25 and the
transcriptional repressor FOXP3 (forkhead box P3). These cells mature and migrate
from the thymus and constitute 5–10% of peripheral T cells in normal mice. Other
populations of antigen-specific regulatory T cells can be induced from naive
CD4 + CD25 - or CD8 + CD25 - T cells in the periphery under the influence of semimature
dendritic cells, interleukin-10 (IL-10), transforming growth factor- (TGF-)
and possibly interferon- (IFN-). The inducible populations of regulatory T cells
include distinct subtypes of CD4 + T cell: T regulatory 1 (T R 1) cells, which secrete
high levels of IL-10, no IL-4 and no or low levels of IFN-; and T helper 3 (T H 3) cells,
which secrete high levels of TGF-. Although CD8 + T cells are normally associated
with cytotoxic T-lymphocyte function and IFN- production, these cells or a subtype
of these cells can secrete IL-10 and have been called CD8 + regulatory T cells.
SL Reiner Cell 129: 33-36; 2007

Mechanism(s) of suppression.
Various molecular and cellular
events have been described to
explain how Treg can suppress
immune responses. They
include: IL-2 gene expression
inhibition, modulation of
costimulatory molecules on APCs
and interaction of LAG3 with
MHC class II molecules (a),
immunosuppressive cytokine
secretion (b), induction of
tryptophan catabolism through
CTLA-4 (c) and cytotoxicity (d).
However, none of those
mechanisms can explain all
aspects of suppression. It is
probable that various
combinations of several
mechanisms are operating,
depending on the milieu and the
type of immune responses. It is
also possible that there might be
a single key mechanism that has
not been found yet (e).
Abbreviations: APC, antigen
presenting cell; TCR, T cell
receptor.

B cells ….

CD4 T-Zelle
CD40L
T-Zell-Hilfe
durch Zytokine
2.Signal:
Quervernetzung der
Ig durch Antigen oder
Aktivierung durch CD40L
CD40
1. Signal:
Bindung des Antigen
an Ig
2. Signal
naive B - Zelle
kein
2. Signal
B-Gedächtniszelle