Signal transducer and activator of transcription 1 in T cells plays an indispensable role in immunity to Leishmania major by mediating Th1 cell homing to the site of infection

Joseph Barbi, Heidi M. Snider, Neeti Bhardwaj, Claudio M. Lezama-Dávila, Joan E. Durbin, Abhay R. Satoskar

Research output: Contribution to journalArticle

Abstract

The signal transducer and activator of transcription 1 (STAT1) signaling pathway mediates the biological functions of IFN-γ. We have previously shown that the STAT1 pathway is indispensable for host resistance against Leishmania major infection. In this study, we examined the role of STAT1 in lymphocytes and specifically CD4+ and CD8+ T cells in mediating immunity against L. major by transferring T cells from wild-type (WT) and STAT1-/- C57BL/6 mice into Rag2-/- C57BL/6 mice. Rag2-/- mice reconstituted with unfractionated STAT1-/- splenocytes (B cells and T cells) failed to mount an efficient Th1 response after L. major infection, produced more IL-4, and developed large lesions full of parasites. In contrast, Rag2-/- mice reconstituted with WT (STAT1+/+) splenocytes mounted a Th1 response and developed self-resolving lesions. Studies using Rag2-/- recipients that received a combination of purified CD4+ and CD8+ T cells from WT or STAT1-/- mice revealed that STAT1 deficiency in CD4 + T cells, but not in CD8+ T cells, leads to development of chronic, nonhealing lesions and systemic dissemination of parasites into the spleen after L. major infection. Further studies using Rag2-/- recipients of WT Thy1.1+ and STAT1-/- Thy1.2+ T cells showed that STAT1 in CD4+ T cells was not required for Th1 differentiation during L. major infection. However, it was critical for up-regulation of CXCR3 on CD4+ T cells and their migration to the regional lymph node and the cutaneous site of infection. Together, these studies indicate that the STAT1 pathway in CD4+ T cells plays a critical role in immunity against L. major by controlling the migration of Th1 cells to the site of infection rather than their generation. Further, they reveal an essential role for CD4+ T cell STAT1 in preventing systemic dissemination of L. major infection.

Original languageEnglish (US)
Pages (from-to)3990-3999
Number of pages10
JournalFASEB Journal
Volume23
Issue number11
DOIs
StatePublished - 2009
Externally publishedYes

Fingerprint

STAT1 Transcription Factor
Leishmania major
Th1 Cells
T-cells
Immunity
T-Lymphocytes
Infection
Inbred C57BL Mouse
Parasites
Lymphocytes
Interleukin-4
Cell Movement

Keywords

  • CXCR3
  • Protozoa

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Genetics
  • Molecular Biology

Cite this

Signal transducer and activator of transcription 1 in T cells plays an indispensable role in immunity to Leishmania major by mediating Th1 cell homing to the site of infection. / Barbi, Joseph; Snider, Heidi M.; Bhardwaj, Neeti; Lezama-Dávila, Claudio M.; Durbin, Joan E.; Satoskar, Abhay R.

In: FASEB Journal, Vol. 23, No. 11, 2009, p. 3990-3999.

Research output: Contribution to journalArticle

Barbi, Joseph ; Snider, Heidi M. ; Bhardwaj, Neeti ; Lezama-Dávila, Claudio M. ; Durbin, Joan E. ; Satoskar, Abhay R. / Signal transducer and activator of transcription 1 in T cells plays an indispensable role in immunity to Leishmania major by mediating Th1 cell homing to the site of infection. In: FASEB Journal. 2009 ; Vol. 23, No. 11. pp. 3990-3999.
@article{9f8cdd3ef0df414ca8ff8cc3af15fcba,
title = "Signal transducer and activator of transcription 1 in T cells plays an indispensable role in immunity to Leishmania major by mediating Th1 cell homing to the site of infection",
abstract = "The signal transducer and activator of transcription 1 (STAT1) signaling pathway mediates the biological functions of IFN-γ. We have previously shown that the STAT1 pathway is indispensable for host resistance against Leishmania major infection. In this study, we examined the role of STAT1 in lymphocytes and specifically CD4+ and CD8+ T cells in mediating immunity against L. major by transferring T cells from wild-type (WT) and STAT1-/- C57BL/6 mice into Rag2-/- C57BL/6 mice. Rag2-/- mice reconstituted with unfractionated STAT1-/- splenocytes (B cells and T cells) failed to mount an efficient Th1 response after L. major infection, produced more IL-4, and developed large lesions full of parasites. In contrast, Rag2-/- mice reconstituted with WT (STAT1+/+) splenocytes mounted a Th1 response and developed self-resolving lesions. Studies using Rag2-/- recipients that received a combination of purified CD4+ and CD8+ T cells from WT or STAT1-/- mice revealed that STAT1 deficiency in CD4 + T cells, but not in CD8+ T cells, leads to development of chronic, nonhealing lesions and systemic dissemination of parasites into the spleen after L. major infection. Further studies using Rag2-/- recipients of WT Thy1.1+ and STAT1-/- Thy1.2+ T cells showed that STAT1 in CD4+ T cells was not required for Th1 differentiation during L. major infection. However, it was critical for up-regulation of CXCR3 on CD4+ T cells and their migration to the regional lymph node and the cutaneous site of infection. Together, these studies indicate that the STAT1 pathway in CD4+ T cells plays a critical role in immunity against L. major by controlling the migration of Th1 cells to the site of infection rather than their generation. Further, they reveal an essential role for CD4+ T cell STAT1 in preventing systemic dissemination of L. major infection.",
keywords = "CXCR3, Protozoa",
author = "Joseph Barbi and Snider, {Heidi M.} and Neeti Bhardwaj and Lezama-D{\'a}vila, {Claudio M.} and Durbin, {Joan E.} and Satoskar, {Abhay R.}",
year = "2009",
doi = "10.1096/fj.09-138057",
language = "English (US)",
volume = "23",
pages = "3990--3999",
journal = "FASEB Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "11",

}

TY - JOUR

T1 - Signal transducer and activator of transcription 1 in T cells plays an indispensable role in immunity to Leishmania major by mediating Th1 cell homing to the site of infection

AU - Barbi, Joseph

AU - Snider, Heidi M.

AU - Bhardwaj, Neeti

AU - Lezama-Dávila, Claudio M.

AU - Durbin, Joan E.

AU - Satoskar, Abhay R.

PY - 2009

Y1 - 2009

N2 - The signal transducer and activator of transcription 1 (STAT1) signaling pathway mediates the biological functions of IFN-γ. We have previously shown that the STAT1 pathway is indispensable for host resistance against Leishmania major infection. In this study, we examined the role of STAT1 in lymphocytes and specifically CD4+ and CD8+ T cells in mediating immunity against L. major by transferring T cells from wild-type (WT) and STAT1-/- C57BL/6 mice into Rag2-/- C57BL/6 mice. Rag2-/- mice reconstituted with unfractionated STAT1-/- splenocytes (B cells and T cells) failed to mount an efficient Th1 response after L. major infection, produced more IL-4, and developed large lesions full of parasites. In contrast, Rag2-/- mice reconstituted with WT (STAT1+/+) splenocytes mounted a Th1 response and developed self-resolving lesions. Studies using Rag2-/- recipients that received a combination of purified CD4+ and CD8+ T cells from WT or STAT1-/- mice revealed that STAT1 deficiency in CD4 + T cells, but not in CD8+ T cells, leads to development of chronic, nonhealing lesions and systemic dissemination of parasites into the spleen after L. major infection. Further studies using Rag2-/- recipients of WT Thy1.1+ and STAT1-/- Thy1.2+ T cells showed that STAT1 in CD4+ T cells was not required for Th1 differentiation during L. major infection. However, it was critical for up-regulation of CXCR3 on CD4+ T cells and their migration to the regional lymph node and the cutaneous site of infection. Together, these studies indicate that the STAT1 pathway in CD4+ T cells plays a critical role in immunity against L. major by controlling the migration of Th1 cells to the site of infection rather than their generation. Further, they reveal an essential role for CD4+ T cell STAT1 in preventing systemic dissemination of L. major infection.

AB - The signal transducer and activator of transcription 1 (STAT1) signaling pathway mediates the biological functions of IFN-γ. We have previously shown that the STAT1 pathway is indispensable for host resistance against Leishmania major infection. In this study, we examined the role of STAT1 in lymphocytes and specifically CD4+ and CD8+ T cells in mediating immunity against L. major by transferring T cells from wild-type (WT) and STAT1-/- C57BL/6 mice into Rag2-/- C57BL/6 mice. Rag2-/- mice reconstituted with unfractionated STAT1-/- splenocytes (B cells and T cells) failed to mount an efficient Th1 response after L. major infection, produced more IL-4, and developed large lesions full of parasites. In contrast, Rag2-/- mice reconstituted with WT (STAT1+/+) splenocytes mounted a Th1 response and developed self-resolving lesions. Studies using Rag2-/- recipients that received a combination of purified CD4+ and CD8+ T cells from WT or STAT1-/- mice revealed that STAT1 deficiency in CD4 + T cells, but not in CD8+ T cells, leads to development of chronic, nonhealing lesions and systemic dissemination of parasites into the spleen after L. major infection. Further studies using Rag2-/- recipients of WT Thy1.1+ and STAT1-/- Thy1.2+ T cells showed that STAT1 in CD4+ T cells was not required for Th1 differentiation during L. major infection. However, it was critical for up-regulation of CXCR3 on CD4+ T cells and their migration to the regional lymph node and the cutaneous site of infection. Together, these studies indicate that the STAT1 pathway in CD4+ T cells plays a critical role in immunity against L. major by controlling the migration of Th1 cells to the site of infection rather than their generation. Further, they reveal an essential role for CD4+ T cell STAT1 in preventing systemic dissemination of L. major infection.

KW - CXCR3

KW - Protozoa

UR - http://www.scopus.com/inward/record.url?scp=70350525361&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=70350525361&partnerID=8YFLogxK

U2 - 10.1096/fj.09-138057

DO - 10.1096/fj.09-138057

M3 - Article

VL - 23

SP - 3990

EP - 3999

JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

IS - 11

ER -