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IDO2 is critical for IDO1-mediated T-cell regulation and exerts a non-redundant
function in inflammation
#MMPMID24402311
Metz R
; Smith C
; DuHadaway JB
; Chandler P
; Baban B
; Merlo LM
; Pigott E
; Keough MP
; Rust S
; Mellor AL
; Mandik-Nayak L
; Muller AJ
; Prendergast GC
Int Immunol
2014[Jul]; 26
(7
): 357-67
PMID24402311
show ga
IDO2 is implicated in tryptophan catabolism and immunity but its physiological
functions are not well established. Here we report the characterization of mice
genetically deficient in IDO2, which develop normally but exhibit defects in
IDO-mediated T-cell regulation and inflammatory responses. Construction of this
strain was prompted in part by our discovery that IDO2 function is attenuated in
macrophages from Ido1 (-/-) mice due to altered message splicing, generating a
functional mosaic with implications for interpreting findings in Ido1 (-/-) mice.
No apparent defects were observed in Ido2 (-/-) mice in embryonic development or
hematopoietic differentiation, with wild-type profiles documented for kynurenine
in blood serum and for immune cells in spleen, lymph nodes, peritoneum, thymus
and bone marrow of naive mice. In contrast, upon immune stimulation we determined
that IDO1-dependent T regulatory cell generation was defective in Ido2 (-/-)
mice, supporting Ido1-Ido2 genetic interaction and establishing a functional role
for Ido2 in immune modulation. Pathophysiologically, both Ido1 (-/-) and Ido2
(-/-) mice displayed reduced skin contact hypersensitivity responses, but
mechanistic distinctions were apparent, with only Ido2 deficiency associated with
a suppression of immune regulatory cytokines that included GM-CSF, G-CSF, IFN-?,
TNF-?, IL-6 and MCP-1/CCL2. Different contributions to inflammation were likewise
indicated by the finding that Ido2 (-/-) mice did not phenocopy Ido1 (-/-) mice
in the reduced susceptibility of the latter to inflammatory skin cancer. Taken
together, our results offer an initial glimpse into immune modulation by IDO2,
revealing its genetic interaction with IDO1 and distinguishing its non-redundant
contributions to inflammation.
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