Linfositos y supreion a interleucina 4

Basophils as a Source of IL-4
In a seminal study, Paul and colleagues at the NIH described
a splenic, non-B, non-T cell source of IL-4 that was apparent
after crosslinking of the high-affinity Fc3RI receptor on cells
(Ben-Sasson et al., 1990). Further, T cell- and B cell-independent
IL-4 secretion could be enhanced by IL-3 and the capacity to
produce IL-4 increased substantially whenassayed after the
induction of Th2-asssociated allergic inflammation, such as in
models of Nippostrongylus brasiliensis infection or immunization
with goat anti-mouse IgD antibody (Conrad et al., 1990; Le Gros
et al., 1990; Seder et al., 1991b). Purification of the responsible
Fc3R+ innate cells from the spleen and bone marrow yielded
a population greatly enriched for basophils, as based onstaining
with alcian blue, histamine content, and their characteristic electron
microscopic appearance (Seder et al., 1991a). Likewise,
considerable data have confirmed the capacity of human basophils
to secrete large amounts of IL-4 and IL-13 after Fc3R1
crosslinking (Falcone et al., 2000).
Despite these early observations, the function of basophils
in vivo remains poorly defined. The recentdevelopment of sensitive
transgenic IL-4 reporter mice has forwarded the field considerably.
While highlighting the potential importance of basophils
as an innate, IL-4-competent population, cells from these mice
provided a surrogate marker that has greatly facilitated the
tracking, isolation, and description of the basophil lineage.
Detailed analysis, combining both flow cytometry profilingand
gene array technology, has resulted in a much more definitive
characterization of basophils. As a result, murine basophils can
now be reliably identified based on a distinct combination of
features, including expression of CD49b (DX5), Fc3RI, and
a characteristic forward-side scatter profile that is slightly more
granular than lymphocytes. Basophils can be distinguished from
mastcellsbythe differentialexpressionof c-kit,which isexpressed
14 Immunity 30, January 16, 2009 ª2009 Elsevier Inc.
Immunity
Review
at lowand highamounts, respectively, on the two cell types. Basophils
are constitutively fluorescent in lines of IL-4 reportermice with
GFPtomark expression fromthe endogenous IL-4gene byvarious
means (Min et al., 2004; Voehringer et al., 2004b).
In summary, thediscovery that basophils are a potent source
of IL-4 induced in response to allergic and parasitic helminth
infections could be explained, more than 10 years later, by the
finding that basophils acquire the capacity to make IL-4 after
stimulation during their development in the bone marrow. The
precise mechanism by which this lineage achieves activation
of the Th2-associated cytokine locus remainsundefined, as
does the functional role of IL-4 generated by basophils during
systemic responses to allergens or helminthes.
Initiating Th2 Differentiation
For more than two decades CD4+ T helper cells have been
categorized into specialized subsets, defined by their distinct
cytokine secretion profiles (Mosmann et al., 1986). Among the
number of factors associated with CD4+ T helper celldifferentiation,
the cytokines present during T cell receptor engagement
and expression of the corresponding cytokine receptors have
proven key determinants of T helper cell fate (Murphy et al.,
2000). It has been long established that IL-4, the hallmark cytokine
produced by Th2 cells, selectively drives the Th2 developmental
program while inhibiting the opposing Th1 pathway,
a process definedin cell-culture systems. Considerable in vitro
data substantiate the importance of IL-4 and the signaling
components, IL-4Ra and STAT6, in this process, although the
initial source of IL-4 and/or additional cues that influence Th2
polarization in vivo have remained elusive.
Recent work has suggested that IL-4 derived from basophils
may play a role in the initiation of Th2 differentiation...