Memory Inflation: Continuous Accumulation of Antiviral CD8+ T Cells Over Time

Abstract

CD8+ T lymphocytes play an important role in the control of intracellular pathogens during both acute and persistent infections. This is particularly true in the case of persistent herpesviruses such as human CMV, which are typified by large virus-specific CD8+ T cell populations during viral latency. To understand the origin of these populations and the factors shaping them over time, we investigated the CD8+ T cell response after murine CMV (MCMV) infection. The kinetics of the acute response were characterized by rapid expansion of activated T cells, followed by a contraction phase. Thereafter, we observed a striking pattern, where MCMV-specific memory CD8+ T cells steadily accumulated over time, with 20% of all CD8+ T cells at 1 year specific for one MCMV epitope. Accumulation of MCMV-specific CD8+ T lymphocytes was seen in all organs tested and was associated with continuous activation of specific CD8+ T lymphocytes, primarily within lymph nodes. The pattern of accumulation was observed in only two of five epitopes tested, and was accompanied by a gradual restriction in usage of the variable region of the TCR β-chain over time. This novel pattern of a virus-specific CD8+ T cell response suggests that continuous or repetitive exposure to Ag can slowly mold memory T cell populations over time. This may be relevant for understanding the evolution of the large human CMV-specific CD8+ T cell populations seen in humans.

Virus‐specific CD8+ T lymphocytes within the normal human liver

“…The localization of cells does not appear to be closely linked to the expression of the chemokine receptors CXCR3 and/or CCR5. This compares to a recent study during the memory phase of an MCMV infection, which showed a relative enrichment of MCMV-specific CD8 + T cells within the liver by a factor of 1.5 [16], compared to mean enrichments of 2.2 for CMV and 4.5 for EBV in our study. We estimate that at any time point, the total number of CMV-or EBV-specific CD8 + T cells in a normal human liver is in the order of 1×10 6 for each single specificity.…”

“…However, the cells did not respond efficiently to the PHA and ionomycin treatment as a positive control to warrant analysis, which was most likely linked to an aspect of long-term cell storage. In an attempt to overcome this technical problem, we used the murine CMV (MCMV) model to analyze tetramer-specific T cell function in the liver, as previously described [16]. Using this model, we observed a strong IFN-+ production in the liver lymphocyte populations analyzed, which was comparable to that in the spleen (Fig.…”

The (gradual) rise of memory inflation

“…These emerged as having “effector‐memory” profiles as judged by the expression pattern of molecules such as CCR7, CD62L, CD28, CD27, and CD127 (all low) 3, 16, 17. This molecular pattern suggests homing to non‐lymphoid tissues and indeed the second feature is accumulation not only in blood and spleen where it was first noted but in many such tissues such as lung and liver, as opposed to lymph nodes 1, 3, 13. The third feature observed was maintained effector functions such as cytokine release—in contrast to exhausted CD8 + T cells 8.…”

“…Some debate still exists as to the nature of the non‐hemopoetic cell required. An obvious site is the lymph node since this is where the cells with high proliferative capacity exist (ie, those with a central memory phenotype) and there is evidence for their reactivation (upregulation of CD69, notably in mesenteric nodes in MCMV models) 1, 3, 50. However, other data (including the adenovirus model accompanied by surgery) suggest alternatives may also exist 33.…”

“…The term T‐cell memory “inflation” was first used 15 years ago to describe a phenomenon seen after infection of inbred mouse strains with murine cytomegalovirus 1. It is a striking phenomenon that was made quite evident by the use of MHC‐peptide tetramers to track responses in the infected animals over time 2, 3, 4.…”