TY - JOUR
T1 - B cell-intrinsic IDO1 regulates humoral immunity to T cell-independent antigens
AU - Shinde, Rahul
AU - Shimoda, Michiko
AU - Chaudhary, Kapil
AU - Liu, Haiyun
AU - Mohamed, Eslam
AU - Bradley, Jillian
AU - Kandala, Sridhar
AU - Li, Xia
AU - Liu, Kebin
AU - McGaha, Tracy L.
N1 - Publisher Copyright:
Copyright © 2015 by The American Association of Immunologists, Inc.
PY - 2015/9/1
Y1 - 2015/9/1
N2 - Humoral responses to nonproteinaceous Ags (i.e., T cell independent [TI]) are a key component of the early response to bacterial and viral infection and a critical driver of systemic autoimmunity. However, mechanisms that regulate TI humoral immunity are poorly defined. In this study, we report that B cell-intrinsic induction of the tryptophan-catabolizing enzyme IDO1 is a key mechanism limiting TI Ab responses. When Ido1-/- mice were immunized with TI Ags, there was a significant increase in Ab titers and formation of extrafollicular Ab-secreting cells compared with controls. This effect was specific to TI Ags, as Ido1 disruption did not affect Ig production after immunization with protein Ags. The effect of IDO1 abrogation was confined to the B cell compartment, as adoptive transfer of Ido1-/- B cells to B cell-deficient mice was sufficient to replicate increased TI responses observed in Ido1-/- mice. Moreover, in vitro activation with TLR ligands or BCR crosslinking rapidly induced Ido1 expression and activity in purified B cells, and Ido1-/- B cells displayed enhanced proliferation and cell survival associated with increased Ig and cytokine production compared with wild-type B cells. Thus, our results demonstrate a novel, B cell-intrinsic, role for IDO1 as a regulator of humoral immunity that has implications for both vaccine design and prevention of autoimmunity.
AB - Humoral responses to nonproteinaceous Ags (i.e., T cell independent [TI]) are a key component of the early response to bacterial and viral infection and a critical driver of systemic autoimmunity. However, mechanisms that regulate TI humoral immunity are poorly defined. In this study, we report that B cell-intrinsic induction of the tryptophan-catabolizing enzyme IDO1 is a key mechanism limiting TI Ab responses. When Ido1-/- mice were immunized with TI Ags, there was a significant increase in Ab titers and formation of extrafollicular Ab-secreting cells compared with controls. This effect was specific to TI Ags, as Ido1 disruption did not affect Ig production after immunization with protein Ags. The effect of IDO1 abrogation was confined to the B cell compartment, as adoptive transfer of Ido1-/- B cells to B cell-deficient mice was sufficient to replicate increased TI responses observed in Ido1-/- mice. Moreover, in vitro activation with TLR ligands or BCR crosslinking rapidly induced Ido1 expression and activity in purified B cells, and Ido1-/- B cells displayed enhanced proliferation and cell survival associated with increased Ig and cytokine production compared with wild-type B cells. Thus, our results demonstrate a novel, B cell-intrinsic, role for IDO1 as a regulator of humoral immunity that has implications for both vaccine design and prevention of autoimmunity.
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U2 - 10.4049/jimmunol.1402854
DO - 10.4049/jimmunol.1402854
M3 - Article
C2 - 26216892
AN - SCOPUS:84940121515
SN - 0022-1767
VL - 195
SP - 2374
EP - 2382
JO - Journal of Immunology
JF - Journal of Immunology
IS - 5
ER -