Contribution of Thy1⁺NK cells to protective IFN-γ production duringSalmonellaTyphimurium infections

Abstract

IFN-γ is critical for immunity against infections with intracellular pathogens, such as Salmonella enterica . However, which of the many cell types capable of producing IFN-γ controls Salmonella infections remains unclear. Using a mouse model of systemic Salmonella infection, we observed that only a lack of all lymphocytes or CD90 (Thy1) + cells, but not the absence of T cells, Retinoic acid-related orphan receptor (ROR)-γt–dependent lymphocytes, (NK)1.1 + cells, natural killer T (NKT), and/or B cells alone, replicated the highly susceptible phenotype of IFN-γ–deficient mice to Salmonella infection. A combination of antibody depletions and adoptive transfer experiments revealed that early protective IFN-γ was provided by Thy1-expressing natural killer (NK) cells and that these cells improved antibacterial immunity through the provision of IFN-γ. Further analysis of NK cells producing IFN-γ in response to Salmonella indicated that less mature NK cells were more efficient at mediating antibacterial effector function than terminally differentiated NK cells. Inspired by recent reports of Thy1 + NK cells contributing to immune memory, we analyzed their role in secondary protection against otherwise lethal WT Salmonella infections. Notably, we observed that a newly generated Salmonella vaccine strain not only conferred superior protection compared with conventional regimens but that this enhanced efficiency of recall immunity was afforded by incorporating CD4 − CD8 − Thy1 + cells into the secondary response. Taken together, these findings demonstrate that Thy1-expressing NK cells play an important role in antibacterial immunity.

Neutrophils Are a Source of Gamma Interferon during Acute Salmonella enterica Serovar Typhimurium Colitis

“…Consistent with this idea, splenic NK cells are a prominent cellular source of innate IFN-␥ production in models of systemic S. Typhimurium infection (12)(13)(14). Furthermore, CD1D-restricted NKT cells contribute to innate IFN-␥ production in the livers and spleens of mice with disseminated S. Typhimurium infection (15,16).…”

Altered IFN-γ–Mediated Immunity and Transcriptional Expression Patterns in N-Ethyl-N-Nitrosourea–Induced STAT4 Mutants Confer Susceptibility to Acute Typhoid-like Disease

“…Previous studies have suggested differing roles of neutrophils, macrophages, T lymphocytes, and NK and NKT cells in contributing to IFN-g production during primary Salmonella infection (47-49, 73, 74). Recently, Kupz et al (75) showed that Thy1-expressing precursor and immature NK cells are critical in antibacterial immunity via IFN-g-dependent control of S. Typhimurium. In addition, NK and NKT cells are reported to be early producers of IFN-g from healthy human adult blood lymphocytes stimulated ex vivo with NTS contributing to protection from bacteremia (76).…”

Cellular Requirements for Systemic Control of Salmonella enterica Serovar Typhimurium Infections in Mice

“…Furthermore, analysis confirmed that T cells are not required for the initiation of the "plateau phase" (43,44) and that NK T cells (35) and B cells (33,34) are not essential for clearance of a primary infection. Important new findings from this comprehensive study include data showing (i) that the IFN-␥ that is required for early control of Salmonella may come from a variety of cell types and that NK cells and memory CD8 ϩ T cells alone are sufficient to produce enough IFN-␥ to enable control of the initial exponential growth of the bacteria (13,14); (ii) that in the absence of CD4 ϩ T cells, CD8 ϩ and DN T cells contribute to the control of S. Typhimurium and prevent mice from becoming moribund due to high bacterial numbers (deficiency of classical, nonclassical, or all CD8 ϩ T cell alone has no impact on the outcome of the infection); and (iii) that IFN-␥ levels at later stages of the infection appear to be a correlate of bacterial burden rather than a mediator of clearance.…”

“…Although previous studies have demonstrated crucial roles for both CD4 ϩ T cells and IFN-␥ in antiSalmonella immunity (7,12,13), until recently it was not clear whether these deficiencies are causally linked. We have recently shown that the production of IFN-␥ by NK cells or memory CD8 ϩ T cells in the absence of all other IFN-␥-producing lymphocytes is an important contributor to early host-protection (13)(14)(15). These results indicated an inherent capacity of non-CD4 immune cells to contribute to anti-Salmonella immunity.…”

“…We used a low-dose infection model with an attenuated S. Typhimurium strain (13,14) carrying a deletion mutation in the aromatic pathway that was modeled on the aroA deletion mutant of S. Typhimurium SL1344, known as SL3261 (16). To focus on the mechanisms involved in clearance from systemic organs and to ensure high reproducibility between experiments, an intravenous infection was used.…”