1: Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15047-52. Epub 2003 Dec 1. 

IL-27 regulates IL-12 responsiveness of naive CD4+ T cells through
Stat1-dependent and -independent mechanisms.

Lucas S, Ghilardi N, Li J, de Sauvage FJ.

Department of Molecular Biology, Genentech, 1 DNA Way, South San Francisco, CA
94080, USA.

IL-27, a novel heterodimeric cytokine produced by antigen-presenting cells,
signals through the T cell cytokine receptor (TCCR)/WSX-1 expressed on naive
CD4+ T cells and natural killer cells. TCCR/WSX-1 deficiency results in delayed
T helper type 1 (TH1) development through an unresolved mechanism. We report
here that IL-27 stimulation in developing murine T helper cells potently induces
the expression of the major TH1-specific transcription factor T-bet and its
downstream target IL-12R beta2, independently of IFN gamma. In addition, IL-27
suppresses basal expression of GATA-3, the critical TH2-specific transcription
factor that inhibits TH1 development by down-regulating signal transducer and
activator of transcription (Stat) 4. IL-27 signaling through TCCR/WSX-1 induces
phosphorylation of Stat1, Stat3, Stat4, and Stat5. Stat1 is required for
suppression of GATA-3, but T-bet induction by IL-27 can also be mediated through
a Stat1-independent pathway. Despite its TH1-like signaling profile, IL-27 is
not sufficient to drive the differentiation of CD4+ T cells into IFN
gamma-producing cells. Similarly, IL-27 induces T-bet expression in primary
natural killer cells, but this does not result in an increase of IFN gamma
production or cytotoxic activity. Therefore, although IL-27 is unable to drive
IFN gamma production on its own, it plays an important role in the early steps
of TH1 commitment by contributing in a paracrine manner to the control of IL-12
responsiveness.

PMID: 14657353 [PubMed - indexed for MEDLINE]


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2: J Immunol. 2000 Mar 15;164(6):3056-64. 

Dominance of IL-12 over IL-4 in gamma delta T cell differentiation leads to
default production of IFN-gamma: failure to down-regulate IL-12 receptor beta
2-chain expression.

Yin Z, Zhang DH, Welte T, Bahtiyar G, Jung S, Liu L, Fu XY, Ray A, Craft J.

Sections of Rheumatology and Pulmonary and Critical Care Medicine, Department of
Medicine, Department of Pathology, and Section of Immunobiology, Yale School of
Medicine, New Haven, CT 06520, USA.

Gamma delta T cells secrete Th1- and Th2-like cytokines that help mediate innate
and acquired immunity. We have addressed the mechanism whereby murine gamma
delta T cells acquire the capacity to differentially produce such cytokines.
Splenic gamma delta T cells could be polarized into IFN-gamma- or IL-4-secreting
cells in vitro; however, in contrast to CD4+ alpha beta T cells, gamma delta T
cells predominantly produced IFN-gamma, even in the presence of IL-4, a finding
independent of genetic background. Like CD4+ Th1 cells, IFN-gamma-producing
cells expressed the IL-12 receptor beta 2-chain after activation in the presence
of IL-12; however, unlike Th2 cells, IL-4-primed gamma delta T cells also
expressed this receptor, even in the absence of IFN-gamma and despite the
presence of the transcription factor GATA-3. IL-12 also induced IL-4-primed
gamma delta T cells to proliferate and to translocate Stat3/Stat4, indicating
signaling through the IL-12 receptor. These molecular events can account for the
predominant production of IFN-gamma by gamma delta T cells in the presence of
IL-12, despite the availability of IL-4. Early and predominant production of
IFN-gamma by gamma delta T cells likely is critical for the roles that these
cells play in protection against intracellular pathogens and in tumor immunity.

PMID: 10706694 [PubMed - indexed for MEDLINE]


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