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IRGM3 contributes to immunopathology and is required for differentiation of antigen-specific effector CD8+ T cells in experimental cerebral malaria.

Publication ,  Journal Article
Guo, J; McQuillan, JA; Yau, B; Tullo, GS; Long, CA; Bertolino, P; Roediger, B; Weninger, W; Taylor, GA; Hunt, NH; Ball, HJ; Mitchell, AJ
Published in: Infect Immun
April 2015

Gamma interferon (IFN-γ) drives antiparasite responses and immunopathology during infection with Plasmodium species. Immunity-related GTPases (IRGs) are a class of IFN-γ-dependent proteins that are essential for cell autonomous immunity to numerous intracellular pathogens. However, it is currently unknown whether IRGs modulate responses during malaria. We have used the Plasmodium berghei ANKA (PbA) model in which mice develop experimental cerebral malaria (ECM) to study the roles of IRGM1 and IRGM3 in immunopathology. Induction of mRNA for Irgm1 and Irgm3 was found in the brains and spleens of infected mice at times of peak IFN-γ production. Irgm3-/- but not Irgm1-/- mice were completely protected from the development of ECM, and this protection was associated with the decreased induction of inflammatory cytokines, as well as decreased recruitment and activation of CD8+ T cells within the brain. Although antigen-specific proliferation of transferred CD8+ T cells was not diminished compared to that of wild-type recipients following PbA infection, T cells transferred into Irgm3-/- recipients showed a striking impairment of effector differentiation. Decreased induction of several inflammatory cytokines and chemokines (interleukin-6, CCL2, CCL3, and CCL4), as well as enhanced mRNA expression of type-I IFNs, was found in the spleens of Irgm3-/- mice at day 4 postinfection. Together, these data suggest that protection from ECM pathology in Irgm3-/- mice occurs due to impaired generation of CD8+ effector function. This defect is nonintrinsic to CD8+ T cells. Instead, diminished T cell responses most likely result from defective initiation of inflammatory responses in myeloid cells.

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Published In

Infect Immun

DOI

EISSN

1098-5522

Publication Date

April 2015

Volume

83

Issue

4

Start / End Page

1406 / 1417

Location

United States

Related Subject Headings

  • RNA, Messenger
  • Plasmodium berghei
  • Microbiology
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Malaria, Cerebral
  • Interleukin-6
  • Interferon-gamma
  • Interferon Type I
 

Citation

APA
Chicago
ICMJE
MLA
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Guo, J., McQuillan, J. A., Yau, B., Tullo, G. S., Long, C. A., Bertolino, P., … Mitchell, A. J. (2015). IRGM3 contributes to immunopathology and is required for differentiation of antigen-specific effector CD8+ T cells in experimental cerebral malaria. Infect Immun, 83(4), 1406–1417. https://doi.org/10.1128/IAI.02701-14
Guo, Jintao, James A. McQuillan, Belinda Yau, Gregory S. Tullo, Carole A. Long, Patrick Bertolino, Ben Roediger, et al. “IRGM3 contributes to immunopathology and is required for differentiation of antigen-specific effector CD8+ T cells in experimental cerebral malaria.Infect Immun 83, no. 4 (April 2015): 1406–17. https://doi.org/10.1128/IAI.02701-14.
Guo J, McQuillan JA, Yau B, Tullo GS, Long CA, Bertolino P, et al. IRGM3 contributes to immunopathology and is required for differentiation of antigen-specific effector CD8+ T cells in experimental cerebral malaria. Infect Immun. 2015 Apr;83(4):1406–17.
Guo, Jintao, et al. “IRGM3 contributes to immunopathology and is required for differentiation of antigen-specific effector CD8+ T cells in experimental cerebral malaria.Infect Immun, vol. 83, no. 4, Apr. 2015, pp. 1406–17. Pubmed, doi:10.1128/IAI.02701-14.
Guo J, McQuillan JA, Yau B, Tullo GS, Long CA, Bertolino P, Roediger B, Weninger W, Taylor GA, Hunt NH, Ball HJ, Mitchell AJ. IRGM3 contributes to immunopathology and is required for differentiation of antigen-specific effector CD8+ T cells in experimental cerebral malaria. Infect Immun. 2015 Apr;83(4):1406–1417.

Published In

Infect Immun

DOI

EISSN

1098-5522

Publication Date

April 2015

Volume

83

Issue

4

Start / End Page

1406 / 1417

Location

United States

Related Subject Headings

  • RNA, Messenger
  • Plasmodium berghei
  • Microbiology
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Malaria, Cerebral
  • Interleukin-6
  • Interferon-gamma
  • Interferon Type I