Transcription factor Batf3 is important for development of CD8⁺ T‐cell response against a phagosomal bacterium regardless of the location of antigen

Abstract

Salmonella enterica serovar Typhimurium (ST) is a virulent intracellular bacterium that conceals itself in the phagosomes of infected cells. Although CD8(+) T cells promote protection against various intracellular pathogens, the role of CD8(+) T cells against virulent ST has been unclear due to early fatality of susceptible (B6) mice. Herein, we generated MHC I-deficient mice on the resistant (129SvJ) and susceptible (Nramp1 transgenic B6) background to evaluate the role of CD8(+) T cells against virulent ST. Our results indicate that CD8(+) T cells have a critical protective role in host survival during infection with virulent ST. As antigen presentation and CD8(+) T-cell activation against phagosomal antigens are considered to operate through the cross-presentation pathway, we have evaluated CD8(+) T-cell response against ST in Batf3-deficient mice that lack CD8α dendritic cells (DCs). Using a recombinant of ST that expresses antigen (ST-OVA) mainly in the phagosomes of infected cells, we show that CD8(+) T-cell response is compromised throughout the duration of infection in Batf3-deficient mice. In contrast, when ST delivers antigen to the cytosol of infected cells (ST-OVA-C), CD8(+) T-cell response against the cytosolic antigen was compromised only in the short term in the absence of CD8α DCs, with wild-type and Batf3-deficient mice generating similar CD8(+) T-cell response in the long term. Thus, Batf3 has an important role in CD8(+) T-cell priming regardless of antigenic location; however, its role is redundant at later time intervals against cytosolic antigen.

Batf2 differentially regulates tissue immunopathology in Type 1 and Type 2 diseases

“…25 In contrast to Lm infection, Batf3 −/− mice were highly susceptible to Salmonella enterica serovar Typhimurium (ST) infection to their reduced ability to produce inflammatory cytokines (TNF, IL-6, and IL-1a) and chemokines (MIP-1a, MIP- 1b) by CD8α DCs, which is required for local CD8 + T cell priming to clear early infection. 26 Notably, both Lm and ST are fast proliferating and cytopathic intracellular pathogens, yet the progression of these diseases was different in Batf3 −/− mice (amelioration in LM versus aggravation in ST). Considering this, the observed discrepancies in the inflammatory responses between Lm and Mtb infection models are therefore unsurprising, given the differential proliferating profile of both pathogens in the course of an infection, as Lm is rapidly proliferating but Mtb slow growing.…”

Salmonella infection: Interplay between the bacteria and host immune system

“…Another report showed that the magnitude of the CD8 T cell response correlates directly with the intracellular proliferation of Salmonella , however the CD8 T cells in this study were inferior due to reduced proliferation, cytotoxic functionality, and cytokine production [92]. It should be noted that while many studies investigating CD8 T cell involvement have used attenuated Salmonella strains, a recent study showed an important role for MHC Class I-dependent CD8 T cells in protection against virulent Salmonella [93]. Taken altogether, it may be too early to assign a functional role to CD8 T cells during salmonellosis, or to dismiss their participation in anti- Salmonella immunity.…”

Culling of APCs by inflammatory cell death pathways restricts TIM3 and PD-1 expression and promotes the survival of primed CD8 T cells

“…Bone marrow-derived DCs (BMDCs) were grown in-vitro as previously described after culturing cells with GM-CSF (5 ng/ml, Empire Genomics, New York, NY, USA). 57 Splenic DCs were purified using PE-CD11c positive selection (Stemcell, Vancouver).…”