Prolonged Antigen Presentation, APC-, and CD8+ T Cell Turnover during Mycobacterial Infection: Comparison withListeria monocytogenes

Abstract

We expressed the CTL epitope of OVA (OVA257–264) in an acute (Listeria monocytogenes (LM)-OVA) and a chronic intracellular pathogen (Mycobacterium bovis (BCG)-OVA), to evaluate the kinetics of Ag presentation. LM-OVA proliferated rapidly in vivo, resulting in profound LM-OVA expansion within the first 24 h of infection, culminating in the generation of a potent CD8+ T cell response, which peaked on day 7 but underwent a rapid attrition subsequently. In contrast, BCG-OVA exhibited reduced growth in vivo, resulting in a delayed CD8+ T cell response that increased progressively with time. Relative to LM-OVA, BCG-OVA induced persistently increased numbers of apoptotic (annexin V+) CD8+ T cells. Ag presentation in vivo was evaluated by transferring Thy1.2+ carboxyfluorescein-labeled OT1 transgenic CD8+ T cells into infected Thy1.1+ congeneic recipient mice. LM-OVA induced rapid Ag presentation that was profound in magnitude, with most of the transferred cells getting activated within 4 days and resulting in a massive accumulation of activated donor CD8+ T cells. In contrast, Ag presentation induced by BCG-OVA was delayed, weaker in magnitude, which peaked around the second week of infection and declined to a low level subsequently. Increasing the dose of BCG-OVA while enhancing the magnitude of Ag presentation did not change the kinetics. Furthermore, a higher dose of BCG-OVA also accelerated the attrition of OVA257–264-specific CD8+ T cells. Relative to LM-OVA, the dendritic cells in BCG-OVA-infected mice were apoptotic for prolonged periods, suggesting that the rapid death of APCs may limit the magnitude of Ag presentation during chronic stages of mycobacterial infection.

Reducing the Stimulation of CD8+ T Cells during Infection with Intracellular Bacteria Promotes Differentiation Primarily into a Central (CD62LhighCD44high) Subset

“…Similarly, monocytes chronically infected with BCG fail to present mycobacterial Ags to T cells (35). These reports support our previous observations that the overall magnitude of Ag presentation during BCG-OVA infection is muted, which does not last appreciably beyond the first few weeks of infection (24). The reduction in Ag presentation during BCG-OVA infection, despite the persistence of the bacterium, was not due to the loss of the OVA gene by the bacterium in vivo (19).…”

“…Thus, Ag presentation during LM-OVA infection occurs rapidly, and interestingly, it persists at reduced levels for 7-10 days. In contrast, BCG-OVA infection induced a low level Ag presentation during the first 4 days, peaked during the second week of infection, and declined to very low levels subsequently (24).…”

“…Similarly, we have reported that BCG-OVA infection results in a delayed and muted Ag presentation (24). LM-OVA induced a massive reduction in CFSE intensity of donor OT-1 CD8 ϩ T cells (OVA 257-264 TCR transgenic cells) within the first 4 days, with Ͼ80% of donor CD8 ϩ T cells reducing their CFSE expression.…”

“…5B). Because the LM-OVA burden peaks between 48 and 72 h after infection (24) and the bacteria are undetectable in the spleens by days 5-7, we determined whether competition for Ag presentation would still occur during the declining phase of LM-OVA infection. Mice were infected with LM-OVA and injected with PBS or OT-1 CD8 ϩ T cells at 72 h postinfection.…”

Rapid Clonal Expansion and Prolonged Maintenance of Memory CD8+ T Cells of the Effector (CD44highCD62Llow) and Central (CD44highCD62Lhigh) Phenotype by an Archaeosome Adjuvant Independent of TLR2

“…The overall weaker stimulation at later times may have supported the presence of a constant population of T CM as well as the slower attrition of the T EM cells. For example, chronic Mycobacterium bovis, bacillus Calmette-Guérin infection, evokes an attenuated infection, and predominantly T CM phenotype of CD8 ϩ T cells (44).…”