Delayed Expansion and Contraction of CD8+ T Cell Response during Infection with VirulentSalmonella typhimurium

Abstract

Ag presentation to CD8+ T cells often commences immediately after infection, which facilitates their rapid expansion and control of infection. Subsequently, the primed cells undergo rapid contraction. We report that this paradigm is not followed during infection with virulent Salmonella enterica, serovar Typhimurium (ST), an intracellular bacterium that replicates within phagosomes of infected cells. Although susceptible mice die rapidly (∼7 days), resistant mice (129×1SvJ) harbor a chronic infection lasting ∼60–90 days. Using rOVA-expressing ST (ST-OVA), we show that T cell priming is considerably delayed in the resistant mice. CD8+ T cells that are induced during ST-OVA infection undergo delayed expansion, which peaks around day 21, and is followed by protracted contraction. Initially, ST-OVA induces a small population of cycling central phenotype (CD62LhighIL-7RαhighCD44high) CD8+ T cells. However, by day 14–21, majority of the primed CD8+ T cells display an effector phenotype (CD62LlowIL-7RαlowCD44high). Subsequently, a progressive increase in the numbers of effector memory phenotype cells (CD62LlowIL-7RαhighCD44high) occurs. This differentiation program remained unchanged after accelerated removal of the pathogen with antibiotics, as majority of the primed cells displayed an effector memory phenotype even at 6 mo postinfection. Despite the chronic infection, CD8+ T cells induced by ST-OVA were functional as they exhibited killing ability and cytokine production. Importantly, even memory CD8+ T cells failed to undergo rapid expansion in response to ST-OVA infection, suggesting a delay in T cell priming during infection with virulent ST-OVA. Thus, phagosomal lifestyle may allow escape from host CD8+ T cell recognition, conferring a survival advantage to the pathogen.

Pregnancy Impairs the Innate Immune Resistance toSalmonella typhimuriumLeading to Rapid Fatal Infection

“…It is also a highly virulent organism which devotes Ͼ4% of its genome to virulence mechanisms (56). Thus, even in the fully competent host, adaptive immunity to Salmonella is substantially delayed (8), making it important for innate immunity to control infection. Consequently, even a slightly deviated and/or delayed cytokine/cellular innate response during pregnancy may lead to catastrophic host outcome.…”

“…ϩ T cell response to ST infection is generally detectable only beyond 7 days of infection (7), whereas CD8 ϩ T cell response is substantially delayed until the second week postinfection (8). Overall, ST appears to have evolved many mechanisms to evade the host immune system and establish chronic infection.…”

Inhibitory Receptor Expression on CD8+ T Cells Is Linked to Functional Responses against Trypanosoma cruzi Antigens in Chronic Chagasic Patients

“…), and parasitic (Toxoplasma gondii and Trypanosoma cruzi) infections, there is a delay in the generation of the CD8 + T cell immune response. In addition, Ag-specific T cells become dysfunctional, express inhibitory receptors, and even fail to control the infection (57)(58)(59)(60)(61)(62)(63)(64). Although this process was initially described for models of chronic viral infections, such as lymphocytic choriomeningitis, HIV, simian immunodeficiency, and HBV and HCV (12), recent studies have shown that this phenomenon also occurs in protozoan infections (65,66).…”

Selective culling of high avidity antigen-specific CD4+ T cells after virulent Salmonella infection

“…19,26 27 and were maintained on a CD45.1 + Rag-1-deficient background. For adoptive transfer, 5 · 10 4 CD4 + T cells from SM1 TCR transgenic mice or 1 · 10 7 to 2 · 10 7 CD4 + T cells from CD45.1 + T cells were intravenously transferred 1 day before infection.…”