Project Details
Description
Abstract
Indoleamine, 2,3-dioxygenase (IDO) is the enzyme that catalyzes the first step of the tryptophan catabolic
kynurenine pathway. The T cell immunosuppressive properties of IDO, mediated through various
metabolites from this pathway (collectively known as kynurenines (Kyn)), are well established. Abundant
evidence shows that IDO-mediated immunosuppressive mechanisms are operative in certain infections and
may compromise optimal immune responses to pathogens. There are two isoforms of IDO in mice and
humans, designated IDO1 and IDO2, which possess overlapping and distinct immunoregulatory functions.
This suggests that the mechanisms by which IDO modulates immune responses are more complex than
has been previously appreciated. This complexity is further compounded by the fact that IDO isoforms are
expressed by a wide variety of cells, and the cellular source of the enzyme can be important in determining
its impact on immune responses. Our observations from analyses of anti-tuberculosis (TB) immunity in
isoform-specific ido1-/- and ido2-/- knockout mice suggest the two enzymes exert shared as well as distinct
functions in regulating the activities of several important CD4+ T cell subsets in the lungs of Mycobacterium
tuberculosis (Mtb)-infected mice. Overall, in the absence of either isoform, the Th1, Th17 and neutrophilic
responses are up-regulated, while the Treg response is attenuated, reflecting the immunosuppressive
property of IDO1 and IDO2. Interestingly, relative to the ido2-/- strain, Mtb-infected ido1-/- mice consistently
display a stronger Th1 and Th17 phenotypes, suggesting that the two isoforms may mediate overlapping
and distinct immunomodulating functions in TB. Of note, BCG immunization of ido1-/- and ido1-/-ido2-/-
mice elicits a Th1 response that is superior to that observed in vaccinated wild-type animals. Importantly,
administration of IDO inhibitors concomitant with BCG immunization augments vaccine-elicited Th1
response. We have also observed that iNKT cell function can be regulated by various immunosuppressive
Kyn species. Finally, study of the ido1-/- mouse involving a high inoculum infection with Mtb revealed an
anti-inflammatory role of this isoform. This notion is further supported by the observation that IDO
expression by non-hematopoietic cells in the lungs is essential for restricting pulmonic inflammation in TB.
This latter result also suggests that specific function of IDO may be cell source-dependent. Based on the
above, we will generate and use a panel of cell- and isoform-specific IDO-deficient mouse strains for the
studies proposed. We will focus on studying myeloid lineage cells, since these express both IDO1 and
IDO2 and possess potent immunoregulatory properties. A range of genetic, pharmacologic and murine
chimera approaches will be used to stringently test the hypothesis that Mtb activates the
immunosuppressive IDO pathway in order to secure an immunosuppressed local environment in infected
tissues, thereby promoting persistence. We will also determine if the IDO pathway plays a role in restricting
the development of excessive lung inflammation in a tuberculous host, and assess ways of manipulating the
IDO pathway and iNKT cell functions to augment vaccine immunogenicity. This proposal brings together the
expertise of three laboratories with a long history of close collaboration to rigorously study the roles of IDO1
and IDO2 in shaping host immunity to Mtb. Understanding the mechanisms of IDO-mediated
immunosuppression will provide useful information for the design of strategies for improving vaccination and
host-directed therapies for prevention and treatment of TB.
Status | Finished |
---|---|
Effective start/end date | 5/1/18 → 4/30/23 |
Funding
- National Institute of Allergy and Infectious Diseases: $806,468.00
- National Institute of Allergy and Infectious Diseases: $806,468.00
- National Institute of Allergy and Infectious Diseases: $806,468.00
- National Institute of Allergy and Infectious Diseases: $302,490.00
- National Institute of Allergy and Infectious Diseases: $503,978.00
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