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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^*,1, Heidi M. Snider^*, Neeti Bhardwaj^*,1, Claudio M. Lezama-Dávila^*, Joan E. Durbin and Abhay R. Satoskar^*,,2

^* Department of Microbiology and

Center for Microbial Interface Biology, The Ohio State University, Columbus, Ohio, USA; and

Department of Pathology, Children’s Hospital, Columbus, Ohio, USA

² Correspondence: Department of Microbiology, The Ohio State University, 484 West 12th Avenue, Columbus, OH 43210, USA. E-mail: satoskar.2{at}osu.edu

The signal transducer and activator of transcription 1 (STAT1) signaling pathway mediates the biological functions of IFN-. 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.—Barbi, J., Snider, H. M., Bhardwaj, N., Lezama-Dávila, C. M., Durbin, J. E., Satoskar, A. 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.

Key Words: CXCR3 • protozoa