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ulatory (Treg) cells. Treg cells devoted to control
immune responses to self-antigens were defined as
“natural Treg cells” including natural killer T (NKT)
and CD4 + CD25 + Foxp3 + T cells. NKT cells represent a
distinct population of T cells showing properties of NK
cells, but expressing α/β TCR, which specifically recognize
glycolipids often expressed by pathogens and
tumour cells (Bendelac 1997). NKT secrete large
amounts of IL-4, IL-10, IFN-γ and transforming growth
factor-β (TGF-β). It is generally accepted that Foxp3 is
a master control gene for the development and function
of natural CD4 + CD25 + Tregs, and there is no doubt
that CD4 + CD25 + Foxp3 + T cells originate from the thymus
as a distinct T cell subset (Sakaguchi 2000, Holm
2004), mainly devoted to control self-reactive T cells
escaped to negative selection, thus ensuring peripheral
tolerance to autoantigens and protecting from autoimmunity.
However, the mechanism by which natural
Tregs exert their suppressive activity is still elusive.
Mechanisms of T-cell polarization
Differentiation of naive Th cells into Th1, Th2 or Th17
effector cells occurs upon direct contact with APCs. A
number of factors are involved in determining the
nature of the effector phenotype that will develop,
including the nature and affinity of the antigen, the type
of TCR signaling, the nature of the coreceptor signals,
and, more importantly, the predominant cytokine environment.
Th cells respond to the products of many signaling
cascades from a wide range of membrane-bound
receptors, including cytokine receptors, and undergo
four steps of development: (i) activation of particular
cytokine genes; (ii) commitment to a certain effector
phenotype (Th1, Th2, or Th17); (iii) inhibition of the
opposing cytokine genes, and (iv) stabilization and
potentiation of the phenotype (Grogan 2001). The
developmental stages of effector T cells are mediated
by different mechanisms, including control of gene
expression by intracellular signaling cascades from cellsurface
receptors and chromatin remodelling.
APCs initiate the first step in the development of adaptive
immunity and tune the T-cell response according to
the nature of the invading pathogens. Pathogen-associated
molecular patterns (PAMPs) of APCs through ligation
of pattern recognition receptors (PRRs) start
APC activation, in particular of DCs (Janeway 2002,
Kapsenberg 2003). The most common receptors
involved are the Toll-like receptors (TLRs), members of
the IL-1R superfamily (Akira 2001), which discriminate
between different types of pathogens. Receptors
on DCs bind inflammation-associated tissue-specific
factors, which are characteristic for the type of tissue
and the pathogen-specific response pattern of that tissue.
The binding of tissue factors also activates DCs
and constitutes an indirect method of pathogeninduced
maturation.Tissue factors include cytokines,
chemokines, eicosanoids, heat-shock proteins and
necrotic cell lipids (Beg 2002). Bone marrow DCs
migrate as immature cells to sites of pathogen invasion,
G. Del Prete - The complexity of the CD4 T-cell response
where pathogens activate their maturation into
immunostimulatory effector cells. Mature DCs migrate
into lymphoid organs and provide naive T cells with
antigen that stimulates specific TCRs, costimulatory
molecules that prevent tolerance, and polarizing factors
that determine which phenotype of effector T-cell will
be produced. DC maturation results in the production
of functionally different effector DC subsets that
release polarizing signals (the most important are
cytokines), which selectively promote the development
of Th1, Th2, or Th17 cells (Reis e Sousa 2001). Mature
effector DCs, which are referred to as DC1, DC2 and
regulatory DC, selectively express cytokines, coreceptors
and other polarizing signals that promote the
development of Th1, Th2 or regulatory T cells, respectively.
The majority of TLRs mediate the development of Th1promoting
DCs (DC1), whereas most of the PRRs that
mediate Th2-cell-inducing DCs (DC2) remain undefined.
However, it has recently been shown that the
synthetic TLR2 ligand Pam3Cys can elicit a Th2-inducing
phenotype in DCs (Redecke 2004). Therefore,
according to the nature of the foreign antigen, DCs
determine the intensity and the functional phenotype of
the immune response generated. The next step in the
development of a Th1 or a Th2 immune response is the
physical interaction between the different activated
DCs and the naive Th cell. An immunological synapse
is formed between T cells and APCs with a dynamic
process occurring when a T-cell comes into physical
contact with the DC (Boes 2002). The activated naive
Th cell then matures into a cell able to perform Th1 or
Th2 functions (Table 1). Whether a Th1 or a Th2
response is induced is determined when TCRs recognize
the specific antigen peptide and induce intracellular
signals, such as protein kinase C (PKC), calcium
ions, nuclear factor-κB, that help generate the appropriate
immune response (Constant 1997, Rogers 1999
, Noble 2000).
Other signals are required for the activation of Th cells
and these are dependent on cell interactions involving
coreceptor molecules on the DC and the T-cell. For
example, CD40, CD80, CD86, the programmed death-
1 ligand (PD-L1), programmed death-2 ligand (PD-L2)
and inducible costimulator ligand (ICOS-L) are
expressed on APCs and their respective binding partners
CD40L, CD28/cytotoxic T lymphocyte antigen-4
(CTLA-4), programmed death-receptor 1 (PD-1), and
ICOS are expressed on T cells. In order to achieve
proper differentiation of the activated naive T cells, Tcell
polarizing cytokines are required. For secretion of
these factors to occur at the optimal time, i.e. when the
DC comes into contact with the T-cell, the DC must be
restimulated by the binding of CD40 to its ligand
(CD40L) on the T-cell membrane (Cella 1996).
Cytokines are the most influential factors that modulate
the T-cell phenotype, and their action involves
intracellular signals transmitted through cytokine
receptors expressed on the T-cell surface. When
cytokines bind to their receptors on naive Th cells, the