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Production and Differentiation of KLRG1+ Effector Subpopulations during Toxoplasma gondii Infection1
* Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912; and
Center for Immunity and Inflammation, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, NJ 07101
IFN-
-producing CD8+ T lymphocytes are essential effector cells that mediate protective immunity during murine toxoplasmosis, and yet their effector development remains poorly characterized. Vaccination with the carbamoyl phosphate synthase (CPS) mutant strain of Toxoplasma gondii was used to examine the CD8+ T cell response in the peritoneal effector site. Four CTL subpopulations with varying effector potentials were defined based on the expression of effector molecules and the cell surface activation markers CD62L and killer cell lectin-like receptor G1 (KLRG1). Further phenotypic analysis revealed that the acquisition of KLRG1 among effector subpopulations correlated with the down-regulation of both IL-7R and CD27, suggesting that KLRG1 marks dominant, end-stage effector cells. Using gene-targeted mice, we tested the in vivo requirements of key IL-12 signaling components for effector CTL differentiation. Contrary to established models of viral and bacterial infection, CD8+ T cell-intrinsic IL-12 signaling was required for the generation of IFN--producing CTLs in response to T. gondii. Importantly, the development of the KLRG1+ effector subpopulations, but not the memory precursor-containing KLRG1– effector subset, was critically reliant on IL-12. Furthermore, IL-12 signaling-dependent T-bet expression was also found to be important for differentiation of KLRG1+ effectors. Our results underscore a vital role for IL-12 in not only the induction of IFN- expression but also in the development of heterogeneous subpopulations of effector CD8+ T cells generated in response to the intracellular parasite T. gondii.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the National Institutes of Health Grant AI 50618 (to G.S.Y.).
2 Address correspondence and reprint requests to Dr. George S. Yap, Department of Medicine, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, Newark, NJ 07101. E-mail address: yapgs{at}umdnj.edu
3 Abbreviations used in this paper: LCMV, lymphocytic choriomeningitis virus; CPS, carbamoyl phosphate synthetase; F (plus roman numeral), fraction; GrB, granzyme B; ICS, intracellular staining; KLRG1, killer cell lectin-like receptor G1; MPEC, memory precursor effector cell; PEC, peritoneal exudate cell; SLEC, short-lived effector cell; WT, wild type.
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