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The Journal of Immunology, 2006, 177: 22-25.
Copyright © 2006 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: STAT1 and T-bet Play Distinct Roles in Determining Outcome of Visceral Leishmaniasis Caused by Leishmania donovani1

Lucia E. Rosas2,*, Heidi M. Snider2,*, Joseph Barbi2,*, Anjali A. Satoskar{dagger}, Geanncarlo Lugo-Villarino||, Tracy Keiser*, Tracy Papenfuss{ddagger}, Joan E. Durbin§, Danuta Radzioch, Laurie H. Glimcher||,# and Abhay R. Satoskar3,*,{ddagger}

* Department of Microbiology, {dagger} Department of Pathology, and {ddagger} Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, OH 43210; § Department of Pediatrics, Children’s Hospital, Columbus, OH 43205; Department of Experimental Medicine and Human Genetics, Montreal General Hospital, Montreal, Canada; || Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115; and # Department of Medicine, Harvard Medical School, Boston, MA 02115


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
T-bet and STAT1 regulate IFN-{gamma} gene transcription in CD4+ T cells, which mediate protection against Leishmania. Here we show that T-bet and STAT1 are required for the induction of an efficient Th1 response during Leishmania donovani infection, but they play distinct roles in determining disease outcome. Both STAT1–/– and T-bet–/– mice failed to mount a Th1 response, but STAT1–/– mice were highly resistant to L. donovani and developed less immunopathology, whereas T-bet–/– mice were highly susceptible and eventually developed liver inflammation. Adoptive cell transfer studies showed that RAG2–/– recipients receiving STAT1+/+ or STAT1–/– T cells developed comparable liver pathology, but those receiving STAT1–/– T cells were significantly more susceptible to infection. These unexpected findings reveal distinct roles for T-bet and STAT1 in mediating host immunity and liver pathology during visceral leishmaniasis.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Interferon-{gamma} is critical for host defense against visceral leishmaniasis (VL)4 caused by Leishmania donovani and Leishmania chagasi (1, 2, 3, 4, 5, 6), and STAT-1 plays a critical role in IFN-{gamma} and IFN-{alpha}beta signaling (7). STAT-1 mediates IFN signaling in macrophages, induces NO production, regulates Th1 differentiation, and is involved in the host defense against pathogens such as Leishmania major, Listeria monocytogenes, and Toxoplasma gondii (8, 9, 10, 11).

T-bet is a key transcription factor that induces IFN-{gamma} production in NK and CD4+ T cells and induces Th1 differentiation in naive T cells and polarized Th2 cells (12, 13, 14, 15, 16). Expression of T-bet in T cells is controlled by IFN-{gamma} via the STAT1-dependent pathway (17). Nonetheless, STAT1 and T-bet are known to play functionally different roles in certain diseases such as experimental autoimmune encephalomyelitis (18).

We compared the roles of STAT1 and T-bet in immunity to L. donovani using STAT1–/– and T-bet–/– mice. T-bet–/– mice failed to mount an efficient Th1 response and showed increased susceptibility to L. donovani. In contrast, STAT1–/– mice were highly resistant to infection despite mounting a poor Th1 response and developed minimal liver pathology. Adoptive T cell transfer studies showed that although STAT1 in T cells was not involved in mediating liver pathology and susceptibility to L. donovani, it was required for controlling parasite growth once the infection was established. This study shows that T-bet and STAT1 play distinct roles in determining outcome of L. donovani infection and reveals an unexpected role of STAT1 in pathogenesis of VL.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Disclosures
 References
 
Animals

STAT1–/– (C.129S-Stat1<tm1Dlv>), T-bet–/– (C.129S6-Tbx21<tm1Glm>), IFN-{gamma}–/– (C.129S7(B6)-Ifng<tm1Ts>), IFN-{alpha}betaR –/– (C.129S2-Ifnar1<tm1Agt>), and IFN-{gamma}IFN-{alpha}betaR –/– (C.129S-Ifng<tm1Ts> Ifnar1<tm1Agt>) mice on BALB/c genetic background were maintained at Ohio State University (Columbus, OH). The wild-type (WT) BALB/c mice were purchased from Taconic Farms. The experiments were performed using 8- to 10-wk-old sex-matched mice.

Parasites and infection protocol

L. donovani (1 Sudan strain) was maintained in Syrian golden hamsters. Mice were infected with 1 x 107 L. donovani amastigotes by i.v. injection into the tail vein. Groups of 4–5 mice were sacrificed on days 15, 30, and 60 postinfection, and parasite loads in the liver and spleen were measured as described previously (19). Tissue sections from the organs of L. donovani-infected mice were stained using H & E and subjected to histopathology. Liver granulomas were enumerated and scored as follows: 1) no reaction; 2) developing; 3) mature; and 4) empty (as described in Ref. 19). At each time point, livers from at least 4–5 individual mice were analyzed in each group.

T cell proliferation assay and cytokine analysis

T cell proliferation was performed as previously described (20). Briefly, 5 x 105 cells were added in quadruplicate to the wells of sterile 96-well, flat-bottom tissue culture plates and stimulated with freeze-thawed L. donovani Ag (20 µg/ml). The proliferation responses were measured by Alamar blue assay (21). Supernatants were collected after 72 h of incubation at 37°C and analyzed for the production of IFN-{gamma}, IL-12 p70, IL-4, and IL-10 by ELISA (BD Pharmingen).

Adoptive T cell transfers and reconstitution of RAG2–/– mice

Spleens were removed aseptically from STAT1–/– and STAT1+/+ mice, and cell suspensions were prepared by gentle teasing. RBCs were lysed using Boyles solution, and the remaining cells were run through a nylon wool column twice to remove B cells. Ninety-eight percent of the recovered cells were found to be T cells when analyzed by flow cytometry. Adoptive transfers were performed by injecting 1 x 107 cells in 100 µl into the tail vein of RAG2–/– or SCID recipients, and mice were infected 2 wk postreconstitution with the parasites.

Statistical analysis

Student’s unpaired t test was used to determine statistical significance of differences in the values. A value of p < 0.05 was considered significant.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
T-bet–/– mice are highly susceptible to L. donovani, but STAT1–/– mice show increased resistance

T-bet and STAT1 are indispensable for host defense against cutaneous leishmaniasis caused by L. major (9, 13). Both T-bet–/– and STAT1–/– mice fail to mount an efficient Th1 response and develop lesions full of parasites (9, 13). In this study, organs from WT and T-bet–/– mice contained a similar number of parasites at day 15, but parasite loads increased dramatically in T-bet–/– mice as the infection progressed. Surprisingly, at all time points the organs from STAT1–/– mice contained significantly fewer amastigotes as compared with other groups (Fig. 1). The differences in liver parasite loads between STAT1–/– and WT mice were evident at 5 days after infection, and those between spleen loads were evident by day 10 postinfection (data not shown). Furthermore, mice lacking IFN-{alpha}betaR, which signals via STAT1 (7, 22), also developed parasite burdens and liver pathology comparable to WT mice, whereas those lacking both IFN-{alpha}betaR and IFN-{gamma} were highly susceptible to infection (data not shown). Together, these results indicate that although T-bet and STAT-1 mediate immunity against L. major, they play distinct roles in the host defense against L. donovani. The results also show that although IFN-{alpha}beta regulates resistance to L. major (23), it is not required for immunity to L. donovani, and STAT1-indepdendent mechanisms may control L. donovani growth in the liver of BALB/c mice.


Figure 1
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  		FIGURE 1. Liver (A) and spleen (B) parasite loads in WT, T-bet–/–, and STAT1–/– mice on days 15, 30, and 60 after L. donovani infection. Results are from one representative experiment of four with similar results. Data is expressed as the mean of LDU ± SEM from at least five mice at each time point; *, p < 0.05.

 
STAT1–/– mice develop minimal or no liver pathology after L. donovani infection

Development of tissue granulomas comprised of macrophages and T cells is a hallmark histopathological feature of hepatic inflammation in VL and is required for the resolution of infection (19).

At all time points, livers and spleens from L. donovani-infected STAT1–/– mice were significantly smaller when compared with WT and T-bet–/– mice. On days 15 and 30, livers from WT mice showed significant inflammation characterized by the formation of mature granulomas surrounding Kupffer cells containing amastigotes (Fig. 2, A–C, and Table I), but these mice spontaneously resolved their inflammation by day 60. The onset of hepatic inflammation was delayed in T-bet–/– mice, but poorly formed granulomas containing heavily parasitized macrophages were visible in these mice on days 30 and 60 (Fig. 2, D–F, and Table I). At all time points, STAT1–/– mice developed minimal or no liver inflammation and displayed only an occasional mature granuloma comprised of lymphocytes and macrophages with few or no parasites (Fig. 2, G–I, and Table I).


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  		Table I. Enumeration of granulomas in infected livers from WT, T-bet–/–, and STAT1–/– micea

 

Figure 2
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  		FIGURE 2. Histopathology of infected livers from WT (A–C), T-bet–/– (D–F), and STAT1–/– (G–I) mice. WT mice developed well-organized mature granulomas (white arrows) with occasional clusters of amastigotes within individual macrophages (A–C). Only an occasional developing granuloma (black arrows) was evident in T-bet–/– mice on day 15 (D), but they developed multiple, poorly formed granulomas (black arrows) by day 30 and thereafter (E and F). In contrast, STAT1–/– mice developed no significant liver pathology and contained only an occasional mature granuloma (white arrows) in their liver (G–I). Magnification was x400. Black arrows indicate developing granuloma.

 
Immunofluorescene microscopy showed that STAT1–/– mice contained fewer macrophages and CD4+ T cells in their livers when compared with WT mice (data not shown). Flow cytometry analysis revealed that STAT1–/– mice contained a greater proportion of CD62L+ but fewer CD69+ T cells in their livers and spleens when compared with WT mice, indicating that STAT1–/– mice contain a smaller proportion of activated T cells in their organs (data not shown). This is most likely because STAT1–/– mice contain few parasites in their secondary lymphoid organs, resulting in reduced priming and activation of T cells. STAT1–/– mice also contained fewer CD11b+ICAM-1+ macrophages and LFA-1+ T cells in their organs (data not shown). These findings show that STAT1–/– mice control parasite burdens in the absence of a significant tissue inflammatory response.

STAT1–/– and T-bet–/– mice mount a poor Th1 response following L. donovani infection

STAT1 and T-bet regulate transcription of the IFN-{gamma} gene in CD4+ Th1 cells, which mediate immunity to Leishmania (2, 24). We compared the production of IL-12 p70, IFN-{gamma}, IL-4, and IL-10 by spleen cells from WT, T-bet–/–, and STAT1–/– mice. STAT1–/– and T-bet–/– mice produced significantly less IFN-{gamma} when compared with WT mice (Fig. 3B). However, T-bet–/– mice produced significantly more IL-12 p70 than STAT1–/– mice, suggesting that STAT1 but not T-bet is involved in regulating IL-12 production (Fig. 3, A and B). STAT1–/– and T-bet–/–mice produced more IL-4 and less IL-10 when compared with WT mice on days 15 and 30, but only the difference in IL-4 levels was statistically significant (Fig. 3, C and D). These findings show that STAT1 deficiency impairs Th1 development and IFN-{gamma} production during L. donovani infection but enhances host resistance. In contrast, lack of T-bet also prevents induction of an efficient Th1 response and impairs resolution of L. donovani infection.


Figure 3
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  		FIGURE 3. Cytokine production by splenocytes from L. donovani-infected WT, T-bet–/–, and STAT1–/– mice stimulated with 20 µg/ml L. donovani Ag. IL-12 p70 (A), IFN-{gamma} (B), IL-4 (C), and IL-10 (D) were measured by ELISA. Data shown are the mean ± SE of triplicates from four or five individual mice per group and are representative of two independent experiments; *, p < 0.05.

 
Although the majority of the pleiotropic effects of IFN-{gamma} are mediated via STAT1, several genes are up-regulated via a STAT1-independent pathway (25). Hence, we examined the course of L. donovani infection in STAT1–/– mice treated with an anti-IFN-{gamma} Ab. Administration of anti-IFN-{gamma} Ab increased susceptibility of WT mice to L. donovani but had no effect on the disease outcome of STAT1–/– mice (mean liver Leishman-Donovan units (LDU) of 284 ± 40 and 447 ± 15 in WT mice treated with control Ab and anti-IFN-{gamma}, respectively, p < 0.05 vs mean liver LDU of 44 ± 18 and 47 ± 17 in STAT1–/– mice treated every 4 days with i. p. inoculation of 500 µg of control Ab and anti-IFN-{gamma} Ab (R46A2, provided by Dr. M. Russell, Harvard School of Public Health, Boston, MA), respectively). These findings show that IFN-{gamma} does not mediate host resistance to L. donovani in STAT1–/– mice via a STAT1-independent mechanism.

RAG2–/– mice reconstituted with WT and STAT1–/– T cells are susceptible to L. donovani and develop liver inflammation

STAT-1 regulates focal adhesion kinase-dependent cell adhesion and migration (26). Hence, we hypothesized that L. donovani infection fails to establish in STAT1–/– mice because of impaired trafficking of monocytes into their organs, because these cells are essential for successful survival and replication of Leishmania in the host. In fact, a recent study showed that peripheral macrophage depletion significantly reduced CNS parasitism and pathology in Trypanosoma cruzi-infected suckling rats (27).

To test our hypothesis, we monitored the course of L. donovani infection in syngenic RAG2–/– mice reconstituted with WT or STAT1–/– T cells. Both groups were significantly more susceptible to L. donovani when compared with STAT1–/– mice and developed comparable liver immunopathology (Fig. 4, A and B, and Table II). However, liver parasite loads were significantly higher in RAG2–/– mice reconstituted with STAT1–/– T cells when compared with those receiving WT T cells (Fig. 4C). Similar results were observed in adoptive transfer studies using SCID recipient mice (data not shown). These findings indicate that selective lack of STAT1 in T cells is not sufficient to reduce susceptibility to L. donovani and prevent hepatic pathology. In fact, they show that STAT1 in T cells is required to restrict parasite growth once the infection is established in the liver.


Figure 4
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  		FIGURE 4. A and B, Histopathology of livers from RAG2–/– mice reconstituted with WT (A) or STAT1–/– (B) T cells on day 30 after L. donovani infection. Black arrows denote mature granuloma. Magnification was x 400. C, Parasite loads in livers from these mice expressed as the mean LDU ± SE; *, p < 0.05.

 

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  		Table II. Enumeration of granulomas in the livers at day 30a

 
In conclusion, the Th1-associated transcription factors T-bet and STAT1 play distinct roles in determining the outcome of L. donovani infection. T-bet is essential for mediating immunity but not liver pathology during L. donovani infection, whereas STAT1 mediates both susceptibility and liver pathology. Because IFN-{gamma}, which signals via STAT1, is critical for the resolution of L. donovani infection, our findings are surprising. Because STAT1 is required to control L. donovani replication in the liver once the infection is established, blocking STAT1 may not be a viable approach to preventing VL-associated pathology without compromising immunity. However, further understanding of why the lack of STAT1 renders susceptible BALB/c mice resistant to L. donovani and blocks pathology may enable us to develop therapeutic strategies to target other components of this pathway.


   Disclosures
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 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
1 This work was supported by National Institutes of Health Grants RO1 AI51823 (to A.R.S.) and PO1 AI056296 (to L.H.G.), National Institute of Dental and Cranial Research Institutional National Research Service Award Grant T32DE14320 (to H.M.S.), a National Science Foundation Graduate Fellowship (to G.L.-V.), and a grant from the Ellison Medical Foundation (to L.H.G.). Back

2 L.E.R., H.M.S., and J. B. contributed equally to this work. Back

3 Address correspondence and reprint requests to Dr. Abhay R. Satoskar, Department of Microbiology, Ohio State University, 484 West 12th Avenue, Columbus, OH 43210. E-mail address: satoskar.2{at}osu.edu Back

4 Abbreviations used in this paper: VL, visceral leishmaniasis; LDU, Leishman-Donovan unit; WT, wild type. Back

Received for publication December 1, 2005. Accepted for publication May 1, 2006.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 

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