impaginato piccolo - Società Italiana di Parassitologia (SoIPa)

Parassitologia 50: 9-16, 2008
The complexity of the CD4 T-cell responses: old and new
T-cell subsets
G. Del Prete
Department of Internal Medicine, University of Florence, Viale Morgagni 85 – 50134 Florence,Italy; phone +39-055-
4378103, Fax 055-417289 e-mail: gdelprete@unifi.it
Introduction
Abbreviations used in the text: Antigen-presenting cell, APC; cytotoxic T lymphocyte antigen-4, CTLA-4;
Dendritic cells, DCs; Helicobacter pylori Neutrophil Activating Protein, HP-NAP; inducible costimulator ligand,
ICOS-L; Interferon, IFN; Interleukin, IL; Janus kinase, JAK; major histocompatibility complex, MHC;
natural killer T cells, NKT; pathogen-associated molecular patterns, PAMPs; pattern recognition receptors,
PRRs; programmed death-1 ligand, PD-L1; receptor, R; signal transducers and activators of transcription,
STAT; T-cell receptor, TCR; Toll-like receptor, TLR; Transforming growth factor, TGF; Tumour necrosis factor,
TNF.
Abstract.The T-cell compartment of the immune system reacts to an enormous variety of antigens, including
self antigens, due to its a wide repertoire of T-cell clones. Self-reactive T cells undergo a negative selection
process resulting in apoptosis of T cells with high affinity for self-peptides. Self-reactive T cells escaped
to negative selection are then controlled by natural T regulatory (Treg) cells. Regulation also controls excessive
effector T-cell responses. Three types of effector T cells are recognized: T helper 1 (Th1) cells, which
protect against intracellular bacteria; Th2 cells, which play a role against parasites; Th17 cells, which would
face extracellular bacteria, but also are involved in autoimmunity. Effector T-cell polarization is determined
by the complex interaction of antigen-presenting cells with naïve T cells and involves a multitude of factors,
including the dominant cytokine environment, costimulatory molecules, type and load of antigen presented
and signaling cascades. The decision for the immune response to go in a certain direction is based not onto
one signal alone, rather onto many different elements acting synergistically, antagonistically and through
feedback loops leading to activation of Th1, Th2, or Th17 responses. Both Th1 and Th2 can be suppressed
by adaptive Treg cells through contact-dependent mechanisms and/or cytokines.
Key words: T-cell polarization, T-cell regulation, Th1, Th2, Th17, Treg
Cells and products of the innate immunity, the B cellmediated
antibody responses and cytotoxic T lymphocytes
are fundamental for protection from pathoges.
However, T helper (Th) cells are the central elements of
the effector branch of the immune system.
Naive T helper (Th) cells are activated by recognition
by their T-cell receptor (TCR) of a peptide antigen in
the context of MHC class II molecules of antigen-presenting
cells (APCs). After activation, Th cells begin to
divide, giving rise to clones of effector cells.
In the last 20 years, CD4 + effector Th cells had been
divided into two main functional subsets, with distinct
cytokine-secretion profiles and unique functional characteristics
for each type. In both mice and humans,
these cells were referred to as Th1 or Th2 cells. A third
subset with a mixed panel of Th1 and Th2 cytokine
secretion and intermediate functional properties was
referred to as Th0 (Mosmann 1986, Del Prete 1991a,
Correspondence: Gianfranco Del Prete
Department of Internal Medicine, University of Florence,
Viale Morgagni 85 – 50134 Florence,Italy;
Tel +39-055-4378103; Fax 055-417289,
e-mail: gdelprete@unifi.it
1991b). Th1 cells secrete interferon (IFN)-γ, and
tumour necrosis factor (TNF)-α and TNF-β, which
make these cells particularly effective in protection
against intracellular pathogens, as well as in elimination
of cancer cells (Kidd 2003). Th2 cells secrete interleukin
(IL)-4, IL-5, IL-10 and IL-13, which up-regulate
antibody production and target a number of parasites.
Th2-derived IL-4 and IL-13 activate B cells to IgE production,
IL-5-induces eosinophilia, and IL-3- and IL-4stimulate
mast cell proliferation and degranulation.
Th2-dominated responses against common environmental
allergens are responsible for allergic disorders
(Romagnani 1997).
Until recently the CD4 effector responses were defined
according to the so-called “Th1/Th2 paradigm”.
However, a third subset of effector CD4 cells, known as
Th17 cells, was recently discovered. Th17 cells secrete
IL-17, IL-6, IL-22 and TNF-α and seem to play a role
in tissue inflammation and activation of neutrophils to
face extracellular bacteria.
The existence of T suppressor (Ts) cells had been suggested
in the past (Gershon 1972; Green 1983).
However, since neither the cells nor their postulated
soluble factors were ever characterized, the entire concept
was underscored for many years. In the last
decade, however, their existence has definitively been
demonstrated and Ts cells have been re-named as T reg-